The byway forms a loop in southwestern Colorado traversing the heart of the San Juan Mountains.

The San Juan Skyway reaches its zenith at Red Mountain Pass at elevation 11,018 feet (3,358 m).

Starting in Durango, Colorado, the largest city on San Juan Skyway, the byway follows U.S. Highway 160 (US 160) west through the town of Mancos to Cortez passing the entrance to Mesa Verde National Park.

From Rico the byway crosses 10,222 ft (3116 m) Lizard Head Pass and enters the Uncompahgre National Forest.

From Ridgway, the byway turns south onto US 550 following the Uncompahgre River into the Victorian mining town of Ouray.

The Alpine Loop National Back Country Byway, a four wheel drive jeep road, takes off in the gorge south of Bear Creek Falls.

Back into the San Juan National Forest the highway descends through the Chattanooga Valley to Silverton.