State Route 221 begins on SR 278 just south of Interstate 80 (I-80) west of downtown Carlin.

East of the central Carlin area, SR 221 turns north to return to I-80, where the route meets its end.

The route was later designated part of US 40 in the original Bureau of Public Roads plan for the U.S. Highway system in 1926.

Later, during the formation of the Interstate Highway System, I-80 would eventually replace SR 1/US 40 through Carlin.

[3] The 1976 edition of the Official Highway map for Nevada was the first not showing the US 40 designation.