Authorities said that the death toll was expected to rise. About 200 people were injured.
The tornado touched down near Henderson, Kentucky, and jumped the Ohio river into Indiana at around 2am.
Annie Groves, the chief deputy coroner for Vanderburgh County, said at least 12 people were killed at the Eastbrook Mobile Home Park in Evansville. She said the death toll was expected to rise because people were trapped in debris at the park, which has about 350 homes.
"They were in trailer homes, homes that were just torn apart by the storm, so they're just now getting in there trying to find people," Ms Groves said. Indiana's homeland security spokeswoman, Pam Bright, said five people were confirmed dead in Warrick County, east of Evansville, where the city of Newburgh was struck.
She said that about 100 homes were destroyed and 125 damaged at the mobile home park.
The tornado developed in a line of thunderstorms that rolled east across the Ohio Valley during the morning. The National Weather Service posted severe thunderstorm warnings for sections of northern Ohio.
Chad Bennett, an assistant fire chief, said that the damage path in Newburgh, eight miles (13km) east of Evansville, was about three-quarters of a mile wide and 20 miles long. He said emergency sirens sounded, but most people did not hear them because it happened in the middle of the night. No deaths were reported in Kentucky.
Mike Roeder, a spokesman for the utility company Vectren, said 25,000 homes were without power, mostly in Warrick County.Reuse content