It is signed as an east–west highway, but its actual routing wanders considerably from north to south as it proceeds across the county.

It heads to the northeast, paralleling a small creek as it progresses through the rural town consisting mostly of cultivated fields.

[4] In Preston, the open fields return as NY 220 follows another waterbody, this time the slightly larger Mill Brook.

The routes split here, with NY 220 turning southeast to cross the Chenango River and the New York, Susquehanna and Western Railroad (NYSW).

Past the railroad, NY 220 heads through unimproved fields to a junction with East River Road.

State maintenance of NY 220 ends just east of the driveway to the home, at which point the road continues onward toward Norwich as CR 32.

[4][5] The New York State Woman's Relief Corps Home (now the New York State Veterans' Home at Oxford), an old soldiers' home dedicated to the care of soldiers and their immediate families, nurses employed by the United States Army, and widows and mothers of soldiers, was constructed on a 165-acre (67 ha) plot of land east of the village of Oxford and opened April 19, 1897.

[2][5] The entirety of NY 220 west of Oxford was closed to traffic in July 1935 as a result of damage caused by severe statewide flooding earlier in the month.

As planned, a 0.5-mile (0.8 km) stretch of NY 220 in Oxford would be rerouted to follow the new structure over the river and a Conrail (now New York, Susquehanna and Western Railroad) line that ran along the riverbank.