The tornado touched down near Henderson, Kentucky, and jumped the Ohio River into Indiana at around 2 a.m.
Indiana homeland security spokeswoman Pam Bright said 15 deaths had been confirmed in the state's southwest corner around Evansville.
Of those killed, Bright said 10 people died on the southeast side of Evansville in the Eastbrook Mobile Home Park, and that victims were still being pulled from the debris by late morning.
Bright said the park, with about 350 homes, was devastated by the twister.
"We're treating the trailer park as a mass disaster area," Eric Williams, chief deputy of the Vanderburgh County sheriff's department, told the Evansville Courier & Press.
Five others were confirmed dead in adjoining Warrick County, east of Evansville, where the Ohio River city of Newburgh was struck after 2 a.m., Bright said.
The tornado developed in a line of thunderstorms that rolled rapidly eastward across the Ohio Valley during the morning. The National Weather Service posted severe thunderstorm warnings for sections of northern Ohio.
The damage path in Newburgh, 8 miles east of Evansville, was about three-quarters of a mile wide and roughly 20 miles long, Assistant Fire Chief Chad Bennett told CNN. He said emergency sirens sounded, but most people didn't hear them because it happened in the middle of the night.
No deaths were reported in Kentucky, said Michelle King, a dispatcher with the Henderson County sheriff's office.
Mike Roeder, a spokesman for utility company Vectren, said 25,000 homes were without power, mostly in Warrick County. There also were reports of natural gas leaks.