The Interstate forms a part of Appalachian Development Highway System Corridor V. U.S. Route 72 Alternate (US 72 Alt.)

The interchange was extant prior to I-565's construction; it served State Route 20 (SR 20), which previously extended eastward into Huntsville.

From the interchange, I-565 takes a brief northerly swing to bypass the town of Mooresville before joining and subsuming the former right-of-way of SR 20 through rural southeastern Limestone County.

Progressing eastward, as the western edge of the city of Madison it diverges slightly to the south of the former SR 20 route, traveling parallel to it a short distance away.

At Governors Drive, I-565 takes a slight turn northward away from the old route and continues through an area generally referred to as "West Huntsville".

It enters a two-mile-long (3.2 km) elevated highway stretch, mainly because of difficulties while planning through Wall Triana Boulevard.

It has an interchange with Memorial Parkway just south of University Drive, and then, gradually curving toward the northeast, passes north of downtown Huntsville and through a former cotton mill district.

At Oakwood Avenue, it subsumes what was once the easternmost 0.5 miles (0.80 km) of Andrew Jackson Way, traveling over Chapman Mountain to its eastern terminus where it joins US 72.

When the Interstate Highway System was first laid out during the mid-1950s, I-65 was routed on a north–south bee line connecting Nashville, Tennessee, with Birmingham, Alabama.

During the late 1950s and through the 1960s, Huntsville underwent massive population growth due to the establishment of the US Army Missile Command at Redstone Arsenal and the new NASA Marshall Space Flight Center.

By the time construction had begun, Huntsville had become one of the most populous cities in the contiguous United States without a freeway connection to the Interstate system.

Phase 1 opened in 1989 and extended from the east side of Mooresville to County Line Road (exit 7, which was originally constructed to serve as a terminus taking traffic between I-565 and SR 20).

Just west of the interchange with Memorial Parkway, the speed limit decreases to 65 mph (105 km/h) and remains so for the entire portion east.

This slightly extended I-565 from the then red light at US 72 to the east end and converted the connection with US 72 from an at-grade intersection into a full interchange.

Construction of building an intersection at Dunlap Boulevard is currently underway, with the exit being built along with areas around the Toyota Field.