Route 25 is a highway in south-eastern Missouri.

Its original northern terminus was at Route 9 in Festus.

Until February 1981,[1] when U.S. Route 412 was designated across the southernmost section, "the Bootheel", thus supplanting Route 25 south and west of Kennett, Route 25 passed Senath and Arbyrd, taking a sharp westward turn and heading across the St. Francis River and the Arkansas border, feeding westward to join the former Arkansas Highway 25 (now U.S. 412) toward Paragould, Arkansas.

The old section of Route 25 south and west of Kennett now bears Missouri supplemental route designations.

A three mile business route of MO 25 exists in Malden.