SAN FRANCISCO—The married couple living in the third-floor, ocean-view apartment were friendly and ambitious. She explored the city, posting selfies on Facebook. He started a small music label at home.

“They were nice people,” said Ann McGlenon, their former landlady. “She’s very sweet. He’s a go-getter.”

Authorities say Candelaria Vazquez and Kia Zolfaghari had darker aspirations. Working from unit 6, the pair built a small enterprise making counterfeit prescription pills, the Drug Enforcement Administration says. They designed pills to resemble legitimate oxycodone tablets, with an important, and potentially dangerous, twist, according to the DEA: Instead of oxycodone, they used the deadly synthetic opioid fentanyl as a main ingredient.

Mr. Zolfaghari worked a pill-press machine in their two-bedroom, 1,100 square-foot apartment, the DEA said, where they also kept an action figure of Walter White, the protagonist of the series “Breaking Bad,” in which a high-school chemistry teacher cooks up batches of methamphetamine.

According to a DEA affidavit, the couple sold the pills to buyers around the U.S., including in Washington state and North Carolina. A federal grand jury in San Francisco indicted them on June 21 on charges including conspiracy to manufacture and distribute fentanyl. Both pleaded not guilty.

Small-scale drug labs are cropping up around the country, as budding home-brew traffickers discover how easy it is to manufacture pills using synthetic opioids to meet a skyrocketing demand. Law enforcement says the phenomenon threatens to atomize the illicit narcotics trade, adding a troubling new dimension for authorities already strained trying to halt larger-scale drug gangs.

Abuse of opioids, including prescription drugs, heroin and synthetic narcotics like fentanyl, has reached crisis proportions. The Centers for Disease Control and Prevention said more than 28,000 people died from opioid-related overdoses in 2014, the last year of nationwide data, more than double the total from a decade earlier.

More-recent figures from individual states compiled by The Wall Street Journal suggest the crisis is getting worse, supercharged by fentanyl, a synthetic drug up to 50 times as powerful as heroin. Ten states—Maine, New Hampshire, Vermont, Rhode Island, Connecticut, Pennsylvania, Maryland, North Carolina, Kentucky and Ohio—saw 12,244 fatal drug overdoses of all kinds in 2015, up 21% from 2014, while fentanyl-related deaths across those states soared 128% to 3,883.

Authorities are investigating roughly a dozen suspected fentanyl pill-making operations in states including California, Tennessee and Utah, according to the DEA and local investigators.

These manufacturers aren’t the usual drug kingpins, and some, such as Mr. Zolfaghari and Ms. Vazquez, have no known cartel ties. Instead, they have all the necessary supplies. Though illegal, anyone can order online ingredients needed to set up shop at home, including mixing agents and pill-pressing equipment.

One kilogram of fentanyl, which runs about $3,500 from a Chinese manufacturer, can yield as many as one million pills, according to the DEA. At a street price of $10 a tablet, that can generate $10 million in sales. And barriers to entry are low. A pill press used to mold powder into a tablet runs roughly $1,000, and a die set to stamp it with markings that mimic prescription medication costs about $130, the DEA says.

“What is scary is that it’s the tip of the iceberg,” says Casey Rettig, a special agent in the DEA’s San Francisco division, referring to the freewheeling nature of some small-scale pill-making operations. “It begs the question for us: Are sellers just going to press anything” into pills?

The arrival of small-scale fentanyl pill makers represents a new phase in the illicit drug trade. A decade ago, fentanyl surfaced as a street drug in the U.S., mixed into the heroin supply. At the time, federal authorities traced it to a lab in Toluca, Mexico, that obtained fentanyl ingredients from suppliers in China, according to the DEA. After Mexican authorities shut the Toluca lab down in 2006, the problem largely petered out.

Around 2013, roughly when authorities were cracking down on pain clinics that sold vast quantities of prescription opioids, bootleg fentanyl started making a comeback on the streets. Some U.S. buyers today are ordering fentanyl online directly from Chinese labs. Catering to the same demand pain clinics once served, new drugmakers are turning fentanyl powder into tablets that often are externally identical to legitimate prescription drugs.

In June, law enforcement in Utah arrested a man who allegedly bought a fentanyl variant online and pressed it into fake oxycodone pills in a motel room in the Salt Lake City suburb of Sandy. In January, authorities arrested a union tradesman accused of making thousands of imitation oxycodone tablets with the fentanyl variant acetyl fentanyl in his Queens, N.Y., home.

Because of a lack of quality control—the pill makers sometimes use kitchen blenders to mix ingredients—the amount of fentanyl in tablets can vary by a factor of 10 or more, according to a lab analysis cited by the DEA. Unsuspecting buyers could end up ingesting something much more powerful than what they were expecting.

Replicas of generic hydrocodone painkiller tablets that actually contained fentanyl caused more than 50 overdoses, including at least 13 deaths, in the Sacramento, Calif., area in March and April. “These people are going down hard, they’re going down extremely fast,” said Timothy Albertson, a toxicologist and internist at UC Davis Medical Center in Sacramento, which received 18 pill victims in eight days, including one who died.

The pills were stamped with “M367,” which made them look like real generic pain tablets sold by Mallinckrodt PLC that are supposed to contain hydrocodone bitartrate and acetaminophen. A company spokeswoman said the company has been working with the DEA concerning the Sacramento probe.

In Tennessee, authorities linked three deaths earlier this year to fentanyl-laced tablets that were made to resemble a brand-name painkiller. Investigators believe multiple pill-making operations function in the state, said Tennessee Bureau of Investigation spokesman Josh DeVine.

At least nine people in Pinellas County, Fla., died between January and March from tablets mimicking an antianxiety medication that instead contained synthetic opioids, said Sheriff Bob Gualtieri. “For all I know, it was some guy in a garage here” making them, he said.

Ms. Vazquez and Mr. Zolfaghari, the San Francisco couple, who are both 40, are unlikely candidates to run a drug lab.

Ms. Vazquez, who goes by “Candy,” studied health information technology at Western Career College in the nearby city of Emeryville nearly a decade ago, according to her Facebook page. Of Filipino heritage, she worked several years ago in a job taking care of elderly people, according to her friend Mae Romano-Dunning.

Mr. Zolfaghari is from Fremont, Calif., and played football in high school and community college, according to his father, Behrooz Zolfaghari, who came to the U.S. from Iran nearly 50 years ago. The younger Mr. Zolfaghari started his own independent hip-hop music label focused on up-and-coming rappers. The label no longer has an operating website.

By about 2010, Mr. Zolfaghari had rented a small house in Richmond, Calif., telling his landlord, Robert Riggs, he worked at a local Honda dealership. “As far as I know he was a nice guy,” Mr. Riggs said.

Mr. Zolfaghari and Ms. Vazquez traveled to Reno, Las Vegas and Beverly Hills together, posting photos of their trips on Ms. Vazquez’s Facebook page. They married in 2013, according to her attorney.

Mr. Zolfaghari was struggling with an addiction to opioids sparked by old football injuries, his father said, which led his son to fentanyl.

In March 2014, likely while living in Richmond, Mr. Zolfaghari started buying pill-making supplies, including cutting and binding agents, to process fentanyl, according to email records reviewed by the DEA.

The agency’s Ms. Rettig declined to address where he allegedly acquired the equipment. She said it is common for manufacturers to order supplies online from China or sometimes through the “darknet”—a restricted part of the internet accessible only with special software. Though it is illegal to import pill presses without notifying the DEA, the agency said Chinese suppliers sometimes ship them in pieces to evade detection.

In early 2015, Ms. Vazquez and Mr. Zolfaghari relocated to a modern apartment in San Francisco’s tranquil Sunset District. They told their new landlady they wanted to improve their credit so they could buy a place of their own.

Mr. Zolfaghari talked about his passion for music. He had high hopes for an album by their friend King Harris, a rapper from Oxnard, Calif., and in September 2015, he filed paperwork with the California Secretary of State for a new venture called Planet Zero Records LLC.

The husband and wife set up their fentanyl pill-making operation after moving in, the DEA says. The tablets Mr. Zolfaghari made were circular, white and stamped “ETH” and “446,” markings seen on some oxycodone pills, according to a DEA affidavit.

Pill-making typically involves mixing fentanyl with a cutting agent such as mannitol, a sugary substance, to dilute its strength, according to Karl Nichols, a special agent in the DEA’s San Francisco division. The manufacturer adds a binding agent to hold the ingredients together and pours the mixture into a funnel on the pill press. A small amount drops into a die set, and with the swing of a handle, the pill press stamps the mixture into a tablet.

During a six-month span, Mr. Zolfaghari sold more than 1,500 fentanyl-laced pills to a confidential source working with the DEA, in deals brokered by their friend, the rapper Mr. Harris, according to the DEA affidavit. The grand jury also indicted Mr. Harris, who has pleaded not guilty.

Ms. Vazquez didn’t return calls seeking comment, and her lawyer, Mark Goldrosen, said he was still reviewing the case. Mr. Harris declined to discuss the case, citing his attorney’s advice. Mr. Zolfaghari’s attorney, Harris Taback, declined to address the charges against his client, who, he recently said, was in court-ordered drug treatment.

On one recorded call, the DEA says, Mr. Harris told the source that Mr. Zolfaghari promised “that he can press 100 out fast as f—.”

Authorities say Mr. Zolfaghari also sold pills on the darknet, including one package sent to Charlotte, N.C. He conducted numerous transactions using bitcoin and appeared to have cashed out over $230,000 in the digital currency, according to a DEA seizure-warrant application. Ms. Vazquez’s role centered on receiving drug proceeds, buying supplies and mailing pill shipments, authorities say.

California’s largest tax-collection agency doesn’t show any reported employer wages for Mr. Zolfaghari for the years 2012 through 2015, according to the seizure-warrant application. But the couple were good tenants who paid their $3,000 monthly rent on time with cashier’s checks, according to their landlady. They once triggered a noise complaint, which they quickly addressed by moving a TV and disconnecting a subwoofer speaker, their landlady said.

In May, Mr. Zolfaghari and Ms. Vazquez celebrated their third wedding anniversary at a Morton’s steakhouse, where a custom-printed menu congratulated them. Mr. Zolfaghari bought his wife flowers and a Louis Vuitton purse. Ms. Vazquez posted pictures on her Facebook page as she went to the hair salon and prepared for their date. “Have fun beautiful couple,” one friend wrote.

That same month, Mr. Zolfaghari’s Planet Zero Records label released “Nightmare on Wolff Street,” an album by Mr. Harris. “We believe we’ll be up for a Grammy,” Mr. Zolfaghari told Ms. McGlenon, his landlady. He sent her a link to listen to the album, whose second track is called “Dope House.”

In a June buy, Mr. Harris ordered 500 pills at a price of $6,000 for a DEA informant, the agency said. After the informant deposited the money in a bank account in Ms. Vazquez’s name, the DEA said, Mr. Zolfaghari texted Mr. Harris, “Got it, had orders for 800 yesterday so I gotta get back to work right now.”

The next day, Mr. Zolfaghari and Mr. Harris met outside the San Francisco apartment. Agents observed Mr. Zolfaghari exit the building wearing a dark beanie cap, sunglasses and a satchel. Mr. Harris opened his car trunk and Mr. Zolfaghari handed him a tan envelope that agents said they later found contained 500 fentanyl-laced tablets.

On June 10, authorities descended on their building, sealed off the street below and arrested the couple, as well as Mr. Harris. A clandestine-lab team from the DEA, outfitted with white hazardous-materials suits and oxygen tanks, entered their apartment.

Inside, investigators found the array of pill-making equipment, according to the seizure-warrant application.

A glass display case contained three luxury watches valued at $70,000. Ms. Vazquez’s “shoe collection was stacked virtually from floor to ceiling,” many with price tags of more than $1,000, the seizure-warrant application says. There was $44,000 in cash in a bedroom and a trove of expensive goods, including Hermès bracelets and Tom Ford handbags. And one Walter White doll.