Motor vehicle accidents killed 33,687 people in 2010 -- well below the 38,364 who died from suicide in the same year, the Centers for Disease Control and Prevention said.
The spike in suicides was seen exclusively among US adults aged 35-64, who saw a 28 percent rise over the last decade, the CDC added.
And the numbers were even more stark for those in their 50s, who saw a nearly 50 percent jump in suicide rates.
"Suicide is a tragedy that is far too common," said CDC Director Tom Frieden. "This report highlights the need to expand our knowledge of risk factors so we can build on prevention programs."
Previous research and prevention efforts had focused on the young and the elderly, but the CDC said the new study indicates the focus should be expanded to the middle-aged.
"It is important for suicide prevention strategies to address the types of stressors that middle-aged Americans might be facing and that can contribute to suicide risk," said Linda Degutis, director of CDC's National Center for Injury Prevention and Control.
In 2010, an average of nearly 18 out of every 100,000 people aged 35-64 died from suicide -- four more than a decade earlier, the CDC said.
Among non-Hispanic Whites and Native Americans, annual suicide rates leaped 40 percent and 65 percent, respectively.
Nearly three times as many men as women in this age group killed themselves: around 27 men compared to eight women per 100,000 in 2010.
And the CDC found that, while most suicides were committed with guns, the number of people dying from suffocation and hanging rose the fastest -- by more than 80 percent -- over the last decade.