Interstate 65 enters the Hoosier state at Jeffersonville and Clarksville.
The section of Interstate 65 in downtown Indianapolis overlaps Interstate 70. The junctions are often referred to as the "North Split" and the "South Split", forming a section of interstate locally known as the "Inner Loop" or "Spaghetti Bowl" due to the visual complexity of the overlapping freeways.
In mid-March 2007, a six mile section of Interstate 70 from the North Split to Interstate 465 east of downtown was restricted to automobiles only for the "Super 70" project, a massive rebuild and expansion of that freeway. Trucks over 13 tons are forced to divert through Interstate 65 if coming from the north and use the circular Interstate 465 to the south to reconnect to Interstate 70 East. Westbound traffic from Interstate 70 must loop north or south along Interstate 465 to get to Interstates 65 or 70. This early part of the project is scheduled for completion in November 2007.
In the summer of 2003, the portion of Interstate 65 that runs concurrently with Interstate 70 was closed to all traffic due to the "HyperFix" project. During that time, a new asphalt surface was installed and the overpasses were upgraded.
Both the Super 70 and HyperFix projects were contracted to Walsh Construction of Chicago, Illinois.
In 1999, the 25 mile (40 km) segment of Interstate 65 between the two Interstate 465 interchanges was renamed the Kenneth "Babyface" Edmonds Highway.
Upon crossing into Lake County, IN over the Kanakkee River, the highway is know as the Casimir Pulaski Memorial Highway. It is known as this from that point to its northern terminus.
The northern terminus of Interstate 65 is only 1/8 mile (0.2 km) north of Interstate 90 (Indiana Toll Road). Prior to 2004, the interchange from Interstate 90 to Interstate 65 required making a physical left turn onto Interstate 65 via a traffic signal; traffic from Interstate 65 to Interstate 90 bypassed the traffic signal via an isolated right-turn lane. It has since been grade-separated.
In Lafayette, the Subaru of Indiana Automotive, Inc. plant is located at the junction of I-65 and SR-38. Supplier ArvinMeritor has several facilities near the highway in Columbus.