Three studies consisting of eighteen small-plot field trials were completed in 2016 and 2017 to determine the biologically effective doses of flumioxazin and pyroxasulfone applied preemergence and to classify their interactions when applied as a mixture for the control of multiple herbicide-resistant (MHR) waterhemp in soybean. The predicted doses of flumioxazin to provide 90% MHR waterhemp control were 59, 100, 147, and 151 g ai ha−1 at 2, 4, 8, and 12 weeks after application (WAA), respectively. The predicted doses of pyroxasulfone to provide 90% MHR waterhemp control were 88, 145, 247, and 274 g ai ha−1 at 2, 4, 8, and 12 WAA, respectively. The co-application of pyroxasulfone and flumioxazin primarily resulted in an additive increase in MHR waterhemp control; however, pyroxasulfone (268 g ai ha–1) plus flumioxazin (211 g ai ha–1) resulted in a synergistic increase in waterhemp control and a synergistic decrease in waterhemp shoot biomass at 4 WAA. The co-application of pyroxasulfone and flumioxazin caused a synergistic increase in soybean injury at 2 weeks after emergence; the injury observed was transient.