The accident took place about 4:30 a.m. Tuesday a mile north of the Whiteland Road exit, Whiteland Fire Department chief Dave Gabbard said.
The accident shut down the interstate for more than three hours.
The man lost control of a small street sweeper he was driving north on I-65. His truck flipped over, and he was thrown from the vehicle, Johnson County Sheriff's Office Chief Deputy Randy Werden said.
The man suffered multiple injuries, including a head injury, Werden said.
Emergency workers pronounced him dead at the scene, Gabbard said.
Police have not yet identified the man, and are notifying his family.
The man was driving from Columbus to Indianapolis when the accident happened. A motorist driving behind him told police that he was driving erratically before the accident. The witness said the vehicle was swerving before going off the road and flipping multiple times, Werden said.
Investigators don't know what caused the crash, he said.