U.S. Route 221 begins its northward journey in the City of Perry at the intersection of US 19-98-Alt 27 at the northern terminus of CR 361A. US Truck Route 221 also begins at this intersection, but runs along US 19-98-ALT 27. North of the terminus of CR 335, the road narrows down to two lanes at the intersection of US 27, which includes another leg of the truck detour. North of US 27, Route 221 crosses a bridge over Spring Creek and then meets a pair of at-grade crossings with railroad line owned by Georgia and Florida Railroad, which leads to a branch of the Georgia Southern and Florida Railway further north. Nearby it passes by a former Live Oak, Perry and Gulf Railroad station and then the Perry City Hall, and more than several blocks north of that point crosses another bridge over Pimple Creek just south of the intersection of County Road 356 (Ash Street). Intersections north of the city limits include County Road 359A, which is also the northern terminus of US Truck Route 221, and later County Road 361. The aforementioned G&F Railroad line meets up with the west side of US 221, but runs parallel with it throughout Taylor County, even as they both approach CR 14 (an extension of SR 14) in Shady Grove.
US 221 and the G&F Railway Line continue to run parallel to each other as they cross the Taylor-Madison County Line, and for the most part tends to intersect only local and private roads of no importance, until it approaches the western terminus of CR 360 (Moseley Hall Road). A local street named Open Sands Loop terminates at both ends of US 221, but the road moves away from the railroad line curving to the northeast just south of the northern terminus of this street. North of the western terminus of Former State Road 158, the road turns back north and becomes a divided highway ahead of the interchange with Interstate 10 at Exit 241. The divided highway ends north of this interchange, and the road continues to wind through the woods of the central Florida Panhandle.
The brown US 221 shield used in Florida prior to 1993
Just before entering the Greenville Town Limits US 21 intersects with County Road 150. US 221 then crosses a former Seaboard Air Line Railroad line that was used by AmtrakSilver Meteor until 2005. The former SAL freight depot lies just to the east of the railroad crossing. As the road approaches the historic Bishop-Andrews Hotel, US 221 turns west onto US 90. Together US 90-221 passes by some local industry and the Haffye Hays Park, a local park that contains a memorial to Ray Charles. The routes cross the G&F Railroad line it ran next to in Perry and Taylor County on the east side of Leggett Street, and a block later US 221 finally leaves US 90 to run north as it is intended to do. One last moderate intersection can be found outside of the town limits in the form of the southern terminus of County Road 140 (Old Equipment Road). North of there. CR 140 is encountered again, but it crosses the road heading to the east toward some cemeteries near CR 150.
Upon crossing the Madison-Jefferson County Line, US 221 changes from the westernmost US route in Madison County, to the easternmost in Jefferson County. The only community resembling a major municipality within the county though is Ashville, and the only major street within the county is the eastern terminus of CR 146, but not the eastern terminus of Ashville Highway, which crosses over into Madison County. One last intersection with a private road north of Ashville can be found before US 221 finally crosses the Georgia State Line, where the road continues onto Georgia State Route 76, while hidden State Road 55 terminates.
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