The MidPoint Cafe was built in the late 1940s or early 1950s as a simple one-room cafe. The building was leased to Zella Crim, a waitress from Oklahoma who wanted to own her own cafe. "Zella's Cafe" operated a small outdoor fire BBQ pit to cook her special barbeque.

In the late 1950s, the business was sold to Dub Edmonds and Jesse Fincher. The new owners expanded the size of the building and named their business, "Jesse's Cafe."

When the Interstate came through the area, Edmonds and Fincher started another location near the Interstate 26-miles away from this location. The Adrian location was sold in 1976. Over the years, the cafe continued to change ownership.

In 1995, the owner of the cafe learned that the cafe was located essentially at the center (mid-point) of historic Route 66. Because of this, the name of the business was changed to, "MidPoint Cafe" and the building was redecorated to the look and feel the cafe had in the 1950s-1960s.

In the late 1990s, a basic sign was installed on the opposite side of Route 66 to mark the mid-point. Over the next several years, the sign was replaced, a small visitor plaza was built, and a large, white, mid-point line was painted on the roadway.

In the early 2000s, PIXAR spent time at the cafe and used it as the inspiration for Flo's V-8 Cafe in Radiator Springs.