In 2016, the latest year for which full data is available, "29 percent of all drug overdose deaths mentioned the involvement of fentanyl," said the report from the National Center for Health Statistics, part of the US Centers for Disease Control and Prevention.
The drug works on the brain like morphine or heroin, but is 50 to 100 times more potent, and can easily lead to overdose.
The rate of drug overdose deaths in the United States has tripled from 1999 through 2016, as the nation grapples with a persistent opioid epidemic.
Fentanyl-related drug overdose deaths have doubled each year from 2013 through 2016, "from 0.6 per 100,000 in 2013 to 1.3 in 2014, 2.6 in 2015, and 5.9 in 2016," said the report.
Meanwhile, deaths from heroin and methamphetamine more than tripled from 2011 to 2016.
Heroin was the top cause of drug overdose death from 2012 to 2015, said the report.
The prescription painkiller Oxycodone ranked highest in 2011.
Cocaine has consistently ranked either second or third in terms of deadliest drugs, followed by methamphetamine.