The Republican lawmaker stopped minutes after the rollover accident Wednesday, helping stabilize the survivors until paramedics arrived.
Frist was about 35 miles from Miami and heading to a family vacation home when a sport utility vehicle going in the other direction rolled over.
All six passengers, including three children, were thrown out as the vehicle rolled. A 10-year-old girl died on the scene; another passenger died later at a hospital.
Frist, R-Tenn., a full time heart and lung surgeon before joining the Senate eight years ago, is replacing Trent Lott, R-Miss., who stepped down as majority leader in December after making a racist comment.
"The Senate majority leader was really instrumental in helping us treat the victims," said Broward Fire-Rescue Assistant Chief Todd Leduc.
The victims were transported to hospitals after about 30 minutes. Three of them were in critical condition early Thursday, and the other two were in fair condition.
"As a doctor, my first instincts are to help, and I was privileged to offer my assistance today at the scene of this horrible accident," Frist said Wednesday night in a statement. "My heart goes out to this family which must face the start of the new year with this terrible tragedy."
In 1998, when a gunman opened fire in the U.S. Capitol, Frist rushed to aid the victims. He treated one man who had been shot in the face and performed CPR on another man with a chest wound.
In 1995, Frist revived a 60-year-old man who collapsed inside a Senate office building.