Waterhemp control in Ontario has increased in complexity due to the evolution of biotypes that are resistant to five herbicide modes of action (Groups 2, 5, 9, 14, and 27 as categorized by the Weed Science Society of America). Four field trials were carried out over a 2-yr period in 2021 and 2022 to assess the control of multiple-herbicide-resistant (MHR) waterhemp biotypes in glyphosate/glufosinate/2,4-D-resistant (GG2R) soybean using one- and two-pass herbicide programs. S-metolachlor/metribuzin, pyroxasulfone/sulfentrazone, pyroxasulfone/flumioxazin, and pyroxasulfone + metribuzin applied preemergence (PRE) controlled MHR waterhemp similarly by 46%, 63%, 60%, and 69%, respectively, at 8 wk after postemergence (POST) application (WAA-B). A one-pass application of 2,4-D choline/glyphosate DMA POST provided greater control of MHR waterhemp than glufosinate. Two-pass herbicide programs of a PRE herbicide followed by (fb) a POST-applied herbicide resulted in greater MHR waterhemp control compared to a single PRE or POST herbicide application. PRE herbicides fb glufosinate or 2,4-D choline/glyphosate DMA POST controlled MHR waterhemp by 74% to 91% and by 84% to 96%, respectively, at 8 WAA-B. Two-pass herbicide applications of an effective PRE residual herbicide fb 2,4-D choline/glyphosate DMA POST in GG2R soybean can effectively manage waterhemp that is resistant to herbicides in Groups 2, 5, 9, 14, and 27.