NY 421 begins at a dead end south of the hamlet of Horseshoe in an isolated part of the town of Piercefield.

The two-lane route heads eastward from the trails, following the southern shore of Horseshoe Lake while traversing the deep woods of Adirondack Park.

For the next 2 miles (3.2 km), the road passes through unabated wilderness as it heads toward the western shoreline of Tupper Lake.

After Paradise Point Road, the highway follows a winding, southeasterly course along Tupper Lake, passing little more than dense forests while crossing over the Bog River near its mouth.

[4] In 1923, the New York State Legislature passed a law authorizing the construction of a highway connecting Route 24 (an unsigned legislative route that is now part of NY 30) to the new Veterans' Mountain Camp, an American Legion camp on Tupper Lake.

[7] The bridge over the Bog River was completed on August 29, 1925, and they announced would be opened for traffic within ten days.

[9] This road was extended from modern NY 30 north to a dead end at Warren Point.

[2][3] On February 22, 1960, the American Legion Mountain Camp Corporation in Albany, New York made a decision to abdicate a right-of-way west of NY 421 to the Delaware and Hudson Railway station at Horseshoe.

[12] NYSDPW let out bids for the project, which would construct a new gravel road with asphalt over the former dirt,[13] with a right-of-way that narrowed to 50 feet (15 m) wide due to state lands on each side.

Because of the use of state lands, the right-of-way owned by the American Legion bypassed issues with construction.

[14] Despite the construction of the new road, the Department of Public Works let out a bid in February 1967 to resurface the new highway at the cost of $149,484.

By 1993, the west end of NY 421 was moved about 1 mile (1.6 km) south to its current location southwest of Horseshoe Lake.

[22] On January 17, 1980, the New York State Department of Transportation announced they would open bids to rebuild a stretch of NY 421 of 1.5 miles (2.4 km).