Six field experiments were conducted to investigate any interaction between pyroxasulfone and flumioxazin on soybean tolerance and control of multiple-herbicide-resistant (MHR) waterhemp in soybean during 2016 and 2017 in Ontario, Canada. There was a synergistic increase in soybean injury with the co-application of pyroxasulfone and flumioxazin at all rates evaluated at 2 weeks after emergence (WAE), the two highest rates evaluated (134/106 and 268/211 g ai ha−1) at 4 WAE, and the highest rate (268/211 g ai ha−1) evaluated at 8 WAE. Soybean injury with all pyroxasulfone and flumioxazin treatments was transient and had no adverse effect on soybean grain yield. Pyroxasulfone applied preemergence (PRE) at 45, 89, 134, and 268 g ai ha−1 controlled MHR waterhemp up to 72, 89, 92, and 95%, respectively. Flumioxazin applied PRE at 35, 70, 106, and 211 g ai ha−1 controlled MHR waterhemp up to 78, 90, 93, and 96%, respectively. Pyroxasulfone/flumioxazin applied PRE at 45/35, 89/70, 134/106, and 268/211 g ai ha−1 controlled MHR waterhemp up to 92, 96, 98 and 100%, respectively. There were no significant antagonistic or synergistic interactions for the control of MHR waterhemp with pyroxasulfone/flumioxazin at rates evaluated except at 268/211 g ai ha−1 which provided a synergistic increase in MHR waterhemp control at 4 WAE. The MHR waterhemp biomass and density reductions followed a similar trend as visible control. Pyroxasulfone/flumioxazin at 268/211 g ai ha−1 caused a synergistic response in biomass reduction (9% difference). Based on these results, there is an additive increase in MHR waterhemp control and potential for synergistic soybean injury with the co-application of pyroxasulfone plus flumioxazin.