The Drug Enforcement Administration (DEA) says they intercepted 379m potentially deadly fentanyl doses, which is just two milligrams.
The DEA described the highly addictive substance, which is 50 times more powerful than heroin, as the deadliest drug threat facing the US.
The agency says most of the fentanyl is trafficked into the US from Mexico.
The DEA says it seized more than 10,000lb (4,500kg) of fentanyl, as well as over 50.6m fentanyl pills that were made to resemble different prescription painkillers.
That is more than double what they seized in 2021.
Most of the drugs were mass-produced at secret factories in Mexico by the Sinaloa and Jalisco drug cartels, which use chemicals sourced in China, the agency said.
The drug is so powerful that a lethal dose is small enough to fit on the tip of a pencil.
More than 100,000 Americans died of drug overdoses last year, and two-thirds were attributed to fentanyl. The amount of fentanyl seized this year was enough to kill all 330 million residents of the US, said the drug agency.
"DEA's top operational priority is to defeat the two Mexican drug cartels - the Sinaloa and Jalisco (CJNG) Cartels - that are primarily responsible for the fentanyl that is killing Americans today," DEA Administrator Anne Milgram said.
In addition to the fentanyl, the DEA also seized 131,000lb of methamphetamine, more than 4,300lb of heroin, and over 444,000lb of cocaine.
-- Courtesy of BBC News