FM 649 begins in the Rio Grande Valley at a junction with US 83 in Garceno. The route travels northward through sparsely populated sections of Starr County before entering Jim Hogg County. In the vicinity of the unincorporated community of Randado, FM 649 has a brief concurrency with SH 16 before resuming its northward journey. The highway enters Webb County and passes through Mirando City before reaching its northern terminus at SH 359 west of Oilton.
