In the midwestern United States, biotypes of giant ragweed resistant to multiple herbicide biochemical sites of action have been identified. Weeds with resistance to multiple herbicides reduce the utility of existing herbicides and necessitate the development of alternative weed control strategies. In two experiments in southeastern Minnesota, we determined the effect of six 3 yr crop-rotation systems containing corn, soybean, wheat, and alfalfa on giant ragweed seedbank depletion and emergence patterns. The six crop-rotation systems included continuous corn, soybean–corn–corn, corn–soybean–corn, soybean–wheat–corn, soybean–alfalfa–corn, and alfalfa–alfalfa–corn. The crop-rotation system had no effect on the amount of seedbank depletion when a zero-weed threshold was maintained, with an average of 96% of the giant ragweed seedbank being depleted within 2 yr. Seedbank depletion occurred primarily through seedling emergence in all crop-rotation systems. However, seedling emergence tended to account for more of the seedbank depletion in rotations containing only corn or soybean compared with rotations with wheat or alfalfa. Giant ragweed emerged early across all treatments, with on average 90% emergence occurring by June 4. Duration of emergence was slightly longer in established alfalfa compared with other cropping systems. These results indicate that corn and soybean rotations are more conducive to giant ragweed emergence than rotations including wheat and alfalfa, and that adopting a zero-weed threshold is a viable approach to depleting the weed seedbank in all crop-rotation systems.