Waterhemp biotypes have evolved resistance to Weed Science Society of America (WSSA) Herbicide Groups 2, 5, 9, 14, and 27 in Ontario Canada, are present in 15 counties, spanning a distance of 800 km across southern Ontario, and cause an average soybean yield loss of 42%. Five field experiments were established in growers’ fields in southwestern Ontario to determine the biologically effective doses of diflufenican (Group 12) applied preemergence (PRE) to control multiple herbicide-resistant waterhemp in soybean. The calculated diflufenican doses to elicit 50, 80, and 95% control of MHR waterhemp were 71, 164, and 304 g ai ha-1 at 2 weeks after herbicide application (WAA); 50, 115, and 214 g ai ha-1 at 4 WAA; and 69, 158, and 294 g ai ha-1 at 8 WAA, respectively. The calculated diflufenican doses that caused a 50, 80, and 95% reduction in MHR waterhemp density were 28, 70, and Non-est. g ai ha-1 and the doses that caused a 50, 80, and 95% reduction in MHR waterhemp biomass were 44, 109, and Non-est. g ai ha-1, respectively. The calculated diflufenican doses that resulted in 50, 80, and 95% of the soybean yield of the industry standard herbicide (flumioxazin/pyroxasulfone) were 3, 12, and 57 g ai ha-1, respectively. Diflufenican (180 g ai ha-1) PRE controlled MHR waterhemp 89, 92, and 85%; metribuzin (300 g ai ha-1) PRE controlled MHR waterhemp 94, 84, and 69%; and flumioxazin/pyroxasulfone (105/134 g ai ha-1) PRE controlled MHR waterhemp 100, 99, and 98% at 2, 4, and 8 WAA, respectively. Diflufenican, metribuzin, and flumioxazin/pyroxasulfone applied PRE reduced MHR waterhemp density 96, 84, and 100% and biomass 93, 67, and 99%, respectively at 8 WAA. Diflufenican, metribuzin, and flumioxazin/pyroxasulfone applied PRE caused 9, 0, and 4% visible soybean injury, respectively but the injury was transient and caused no adverse effect on seed moisture content or seed yield of soybean. This study concludes that diflufenican and metribuzin applied PRE provide comparable MHR waterhemp control; however, control was lower than flumioxazin/pyroxasulfone.