SR-100 begins with an intersection with US-64 and passes south of Whiteville. Then SR-100 leaves Whiteville heading east but slightly northward. The route crosses the Hatchie River, still in Hardeman County. State Route 100 passes an intersection with SR-138 near Toone. Following this it passes over SR-18 and shortly thereafter enters Chester County. SR-100 now enters a hilly area of western Tennessee and passes Chickasaw State Park before it intersects US-45 in Henderson. Just to the east of Henderson it crosses the South Fork of the Forked Deer River within a few miles of its inception. After leaving Chester County it enters Henderson County and intersects SR-22 before passing through Scotts Hill. Scotts Hill resides in Henderson County as well as Decatur County. Once in Decatur County SR-100 intersects with SR-69 and then passes through Decaturville which is the county seat and then Perryville. SR-100 then joins with US-412 and crosses the Tennessee River on the Alvin C. York Bridge into Middle Tennessee. SR-100 leaves US-412 just east of Linden in Perry County and goes through Centerville in Hickman County, crossing the Duck River immediately afterwards. SR-100 then enters Williamson County and intersects SR-840, It then enters Davidson County. Then it has an interchange with the Natchez Trace Parkway at the Parkway's northern terminus. It then passes northwest of Percy Warner Park to end at US-70S.
Prior to construction of Interstate 40, SR 100 (in conjunction U.S. 64 between Bartlett and Whiteville) was a customarily traveled route between Memphis and Nashville but today serves primarily local traffic.