Waterhemp is a dioecious species with wide genetic diversity which has enabled it to evolve resistance to several commonly used herbicide groups in North America. Five field trials were established in Ontario to ascertain the biologically effective doses of diflufenican, a new Group 12 herbicide applied preemergence for control of multiple herbicide–resistant (MHR) waterhemp in corn. Based on regression analysis, the predicted diflufenican doses to elicit 50%, 80%, and 95% MHR waterhemp control were 99, 225, and 417 g ai ha−1, respectively, at 2 wk after application (WAA); 73, 169, and 314 g ai ha−1, respectively, at 4 WAA; and 76, 215, and — (meaning the effective dose was beyond the set of doses in this study) g ai ha−1, respectively, at 8 WAA. The predicted diflufenican doses that would cause a 50%, 80%, and 95% decreases in MHR waterhemp density were 42, 123, and — g ai ha−1; and MHR waterhemp biomass were 72, 167, and 310 g ai ha−1, respectively, at 8 WAA. Diflufenican applied preemergence at 150 g ai ha−1 controlled MHR waterhemp by 64%, 79%, and 73% at 2, 4, and 8 WAA, respectively. Isoxaflutole + atrazine applied preemergence at 105 + 1,060 g ai ha−1 controlled MHR waterhemp by 98%, 98%, and 97% at 2, 4, and 8 WAA, respectively; and S-metolachlor/mesotrione/bicyclopyrone/atrazine applied preemergence at 1,259/140/35/588 g ai ha−1 controlled MHR waterhemp by 100%, 100%, and 99% at 2, 4, and 8 WAA, respectively. Diflufenican applied preemergence reduced MHR waterhemp density and biomass by 83%; in contrast, isoxaflutole + atrazine and S-metolachlor/mesotrione/bicyclopyrone/atrazine reduced MHR waterhemp density and biomass by 99%. All treatments evaluated caused either no, or minimal, corn injury and resulted in corn yield that was similar with the weed-free control. Results indicate that diflufenican applied alone preemergence does not provide superior MHR waterhemp control over the commonly used herbicides isoxaflutole + atrazine or S-metolachlor/mesotrione/bicyclopyrone/atrazine; however, there is potential for using diflufenican as part of an integrated weed management strategy for the control of MHR waterhemp control in corn.