SR 221 begins in downtown Alamo at an intersection with SR 54 and SR 88. It goes east through neighborhoods as E Church Street before leaving Alamo and passing through farmland and rural areas as Alamo Gadsden Road. It goes due east for several miles, where it crosses over a large creek, before turning southeast at a Y-Intersection with EmersonRoad to enter Gadsden. The highway enters town along Quincy Street and passes by some homes before coming to an end at an intersection with US 70A/US 79/SR 76. The entire route of SR 221 is a two-lane highway.