State Route 81 is a diagonal route oriented generally from southwest to northeast. Its southwest terminus is at US 19/US 41 in Henry County, and its northeast terminus is at US 29 Business in Winder in Barrow County. Most of it follows loosely the southeastern and eastern third of what could be about a 200-mile (320 km) beltway around Atlanta (three times the length of Interstate 285, the beltway around Atlanta in the picture to the right).

From its southwestern terminus, at US 19 and 41, SR 81 travels east to McDonough. It crosses Interstate 75 at exit 218 while concurrent with SR 20; this concurrency ends in eastern McDonough. SR 81 then proceeds northeastward to the Newton County seat of Covington, crossing over Interstate 20 with no interchange. The route then continues north to Loganville, concurrent again with SR 20 for less than a mile before turning northeast toward its end in Winder.

In Henry County, SR 81 is signed as an east–west route; signage changes to north–south at or near the Newton County line.