The initial investigation indicates that the man, identified as 37-year-old Frederick D. Felder, was driving a freightliner semi pulling a box trailer southbound on I-65 near mile marker 43 in Jackson County when, for an unknown reason, the vehicle left the west side of the roadway, according to Indiana State Police said.
The semi then struck trees and a fence before coming to a rest, police said.
Felder was pronounced dead at the scene.
Police said the investigation is ongoing to determine if Felder died as a result of the collision or if a medical issued played a role in the crash.
The right lane of I-65 Southbound was closed through the area for several hours for crash investigation and cleanup.