The vote divided Democrats and showed the political difficulties in trying to tackle the opioid crisis. The legislation now moves to the Senate, where its fate is uncertain.
Many of the House Democrats who voted in favor of the bill came from swing districts, eager to go on record as supporting legislation intended to crack down on synthetic opioids.
The HALT Fentanyl Act passed 289-133, with 74 Democrats joining all but one Republican.
The Biden administration said it supported the bill earlier this week, while also calling on Congress to pass its other recommendations, like narrower mandatory minimum sentences.
Fentanyl is a synthetic opioid, but it is approved by the Food and Drug Administration for some pain management so it is classified as Schedule II.
Fentanyl-related substances are chemically altered to be similar to but not exactly like fentanyl, making it difficult for authorities to tell if a substance was produced legally.
The measure would mean mandatory harsh jail sentences for fentanyl-related drug crimes, which Democrats and public health groups objected to.
They argued it's another example of overcriminalization, with more focus on incarceration than prevention, treatment and recovery.
"We simply cannot incarcerate our way out of a public health crisis," said Rep. Frank Pallone Jr. (N.J.), the top Democrat on the Energy and Commerce Committee.
"This war on drugs — mandatory sentencing, incarcerate everybody — has not worked," Pallone said.
Republicans assert fentanyl and fentanyl-related substances are pouring across the border. They said the legislation, introduced by Rep. Morgan Griffith (R-Va.), aims to curb overdose deaths and protect Americans by giving law enforcement the tools needed to fight those drugs.
"We should vote to advance this bill that we agree on and that does help stop the bad guys," Griffith said. "Once fentanyl analogues are permanently made Schedule I, Congress can build off this and deal with the illicit crisis."
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