Iowa Highway 21 is a state highway that runs from north to south in central Iowa. It has a length of 97 miles (156 km). Iowa Highway 21 has its southern terminus at Iowa Highway 149 west of Hedrick and its northern terminus at a freeway interchange with U.S. Highway 20 in Waterloo.

Iowa Highway 21 begins one mile (1.6 km) west of Hedrick and goes north through Delta before intersecting Iowa Highway 92. It proceeds through What Cheer before intersecting Iowa Highway 22 west of Thornburg. It continues north to Deep River where it intersects Iowa Highway 85. After passing through Guernsey, it then intersects Interstate 80, then meets U.S. Highway 6. It overlaps with U.S. 6 going eastward, then turns north near Victor. It then intersects Iowa Highway 212 before entering Belle Plaine, then intersects U.S. Highway 30. It goes north to Dysart, where it turns west, overlapping with Iowa Highway 8. It then turns north and ends at U.S. Highway 20 at the southern city limit of Waterloo.

The current version of Iowa Highway 21 is the second occurrence of the route number in the state. The first one went north from Ida Grove to the Minnesota border and was eventually replaced by U.S. Highway 59.

The current Iowa Highway 21 was created in October 1934 and went between Victor and Dysart. It was extended south in 1939 to from Victor to Iowa 92, north from Dysart to U.S. 20 in Waterloo in 1969, and south again from Iowa 92 to Iowa 149 in 1980.