The House passed a bill Thursday that would put illicit fentanyl and its chemical cousins on the most restrictive list of drugs, clearing the way for President Trump’s signature on legislation that bedeviled Congress for years.

Lawmakers voted, 321-104, in favor of the HALT Fentanyl Act. More than 100 Democrats joined most Republicans in supporting the legislation.

The bill would permanently place fentanyl-related substances on Schedule I, instead of keeping it there under temporary scheduling authority.

Fentanyl is a synthetic opioid that is fueling the U.S. drug overdose crisis. Yet Congress has struggled for years to pass legislation that would keep illicit forms of it on the Schedule I list of drugs that have no accepted medical use and a high potential for abuse.

Experts say permanent, rather than temporary, scheduling would result in efficient prosecutions and consistent penalties under guidelines from the U.S. Sentencing Commission while sending a signal to China and Mexico that America is serious about tackling the fentanyl problem as it pressures those nations to do more.

Rep. Morgan Griffith, Virginia Republican, said the bill would prevent Mexican cartels from tweaking chemical compounds to skirt American drug laws and regulations.

“We stop it. We stop them using that technique to get around the law,” said Mr. Griffith, who led the legislative effort with Rep. Bob Latta, Ohio Republican.

The House easily passed the HALT Fentanyl Act on a bipartisan vote in March, giving the effort momentum.

The Senate passed its version of the bill, so as a technical matter, the House had to pass the bill again before it could reach Mr. Trump for his signature.

Illicit fentanyl is made in clandestine labs and has an array of chemical analogs. It’s tough for U.S. laws to keep up with every form, so the HALT Fentanyl Act seeks to cover all of the illicit supply and make it easier for prosecutors to win cases.

Sponsors say the bill would not affect the legal use of fentanyl as a long-standing painkiller or impede research into the drug.

Some Democrats have been leery of permanent scheduling, saying the legislation could result in over-incarceration of drug offenders instead of attacking the root causes of drug addiction.

“It only exacerbates their condition. It leads to individuals being incarcerated longer, and they don’t get the treatment,” said Rep. Frank Pallone, New Jersey Democrat.

He scolded the GOP for proposed cuts to health care programs.

“Republicans are going to claim today that they are addressing the opioid overdose crisis with this bill, but this is nothing but a distraction from the fact that Republicans continue to silently stand by and allow the Trump administration to gut our public health agencies,” he said.

Rates of overdose deaths started to decline noticeably during the latter years of the Biden administration, a trend Democrats attribute to better treatment options and the prevalence of naloxone, an overdose-reversing drug.

Still, more than 77,000 people died of overdoses in the 12 months ending in January, according to the latest provisional data.

Grieving parents of children killed by overdoses lobbied Congress to pass the HALT Fentanyl Act, saying there wasn’t a moment to lose.

Mr. Trump has called for a crackdown on fentanyl trafficking across U.S. borders.

He imposed a 25% tariff on goods from Canada and Mexico, saying they had not done enough to stem trafficking, although many products are exempt under the U.S.-Mexico-Canada trade agreement.