SR 220 runs through a series of small towns, with connecting routes leading to larger population centers such as Augusta, Waterville, and Bangor to the east and west.

The highways cross into the town of Liberty in Waldo County, where SR 105 splits off to the southeast after a 2.49-mile (4.01 km) concurrency.

The road enters the town of Troy and SR 220 splits off to the north, turning briefly east before returning to a northerly heading.

In the 1930s, the route was extended to SR 9 in Unity, then again through Troy and Detroit to its modern terminus at Hurd's Corner in Palmyra, to a total length of 76 miles (122 km).

This was remedied in 1949 when SR 220 was truncated to Friendship at the southern tip of the "V," cutting 9.5 miles (15.3 km) from its length.