The route starts at the Alabama state line, and travels northwestward to Columbus.

[4] At Pickensville Road, MS 69 travels north into Columbus, and intersects Fabritek Drive, the entrance to Columbus-Lowndes County Airport.

[1] A gravel road from Columbus to the Mississippi–Alabama state line has existed since 1928,[8] and it was designated as MS 69 by 1941.

[9][10] A $296,187.71 (equivalent to $3,476,788 in 2023) contract awarded by the Mississippi State Highway Commission in 1951 was used to grade the road, add drainage, culverts, and bridges to the route.

[11] The road was paved with asphalt by 1953,[12][13] after being proposed four years earlier by the city of Columbus' Chamber of Commerce.

[14] The highway caught on fire in 1957, after a wagon carrying coal tar spilled its contents, destroying multiple telephone lines.