Iowa 64 begins at an interchange with US 151 in Anamosa. West of the interchange, the road is County Road E28, which becomes Third Street in Anamosa, while to the east, Iowa 64 begins its eastward trek. It leaves Anamosa heading to the south-southeast. After an S curve that takes the road to the south and then back east, the highway passes Antioch School, which Iowa painter Grant Wood attended for four years. The highway rises Iowa 38 overlaps Iowa 64 for the next before splitting off to the north. Iowa 64 continues east for another and arrives in the town of Wyoming. Upon arriving in Wyoming, Iowa 64 meets with another north–south state highway, this time Iowa 136. At the eastern end of Wyoming, Iowa 64 / Iowa 136 come to a T intersection where the original stretch of Iowa 64 comes to an end. Iowa 136 splits off to the south, while Iowa 64 splits off to the north very briefly before curving eastbound once again. after leaving Wyoming, Iowa 64 enters Jackson County. Iowa 64 passes through the small towns of Monmouth and Baldwin and bypasses the village of Nashville before arriving in Maquoketa, the seat of Jackson County. Iowa 64 intersects US 61 in western Maquoketa. The stretch of Iowa 64 between US 61 and Main Street in Maquoketa is a part of US 61 Business. At the eastern city limits of Maquoketa, Iowa 64 intersects with Iowa 62 which heads north-northeast from Maquoketa towards Bellevue. After Maquoketa, Iowa 64 continues east through rolling farmland before descending into the Goose Lake Channel and intersects CR Z20, formerly Iowa 113, near Spragueville. Iowa 64 leaves the Goose Lake Channel east of Preston. About east of Miles, Iowa 64 meets US 67, which joins Iowa 64 from the south for its last. US 67 ends at the intersection with US 52 west of Sabula. Iowa 64 and US 52 overlap each other for their last in Iowa. Before entering Sabula, US 52 / Iowa 64 cross the Mississippi River backwater Sabula Lakes causeway. North of Sabula, the US 52 / Iowa 64 causeway divides the Mississippi River from Sheepshead Bay, another backwater area. At this point, US 52 / Iowa 64, directionally signed south and east, respectively, are heading north. US 52 / Iowa 64 turn east and cross the main channel of the Mississippi River on the Dale GardnerVeterans Memorial Bridge, becoming US 52 / Illinois Route 64. Immediately after entering Illinois at Savanna, US 52/ IL 64 intersect IL 84. Illinois Route 64 provides a direct link to Chicago.