U.S. Federal Route 278 runs east-west across Pontotoc County. From the Lafayette/Pontotoc County Line to west of Pontotoc, this is a four-lane divided highway. West of Pontotoc, the four-lane highway goes to the north of the town as Mississippi State Route 76. Through Pontotoc, to the Pontotoc/Lee County Line, this is a two-lane highway. U.S. Rt. 278 passes through the following town in Pontotoc County. Pontotoc
U.S. Rt. 278 is multi-plexed in Pontotoc County. Mississippi State Route 6, through Pontotoc County.