The Calfkiller River rises on the Cumberland Plateau of Tennessee just south of Interstate 40 near the town of Monterey in Putnam County. Several of the tributaries which coalesce to form the stream are impounded, including one which forms Monterey Lake, which is readily visible from Interstate 40 and U.S. Highway 70 North.

Tennessee Highway 84 runs down the Calfkiller Valley, generally south. A small community called Calfkiller is located partway down the valley. A large cavern, mined for saltpeter by Confederates during the Civil War, is nearby. The river and the highway then cross into White County, the valley widening somewhat and becoming less steep. The Calfkiller essentially bisects the town of Sparta, the only town of any size along its course and the seat of White County and the southern terminus of Tennessee Highway 84, and continues generally southward, meandering a few times before reaching its confluence with the Caney Fork River. The Caney Fork is, at this point, the line between White County and Van Buren County, and the Calfkiller enters it just east of the bridge on old Tennessee Highway 111.