Abstract Waterhemp [ Amaranthus tuberculatus (Moq.) J.D. Sauer] is one of the most problematic weeds in soybean [ Glycine max (L.) Merr.] production in the Midwestern United States. In recent years, the adoption of soybean resistant to dicamba, 2,4‐D, and/or glufosinate have enabled the use of these herbicides to improve control of problematic weeds. Field experiments were conducted in Indiana in 2021 and 2022 to determine effective herbicide programs for controlling a waterhemp population resistant to herbicides in Weed Science Society of America (WSSA) Groups 2, 4, 5, 9, and 14. Two soybean varieties, one resistant to dicamba, glufosinate, and glyphosate, and the other resistant to 2,4‐D, glufosinate, and glyphosate were evaluated. Preemergence applications included an auxin herbicide, either 2,4‐D or dicamba, applied with pyroxasulfone and flumioxazin. Postemergence applications included combinations of 2,4‐D or dicamba, glyphosate, and glufosinate. No more than 6% soybean injury from all postemergence applications was observed in 2021 and no injury was observed in 2022. By 21 days after the second postemergence application, two‐pass herbicide programs increased waterhemp control by at least 30% compared to one‐pass systems. Comparatively, two pass postemergence programs were more effective in 2021 and preemergence followed by postemergence programs were more effective in 2022. Control of waterhemp with 2,4‐D and dicamba was similar in 2021; however, 2,4‐D was more effective than dicamba in 2022, indicating the diminishing utility of dicamba in this field. Results from this study suggest that effective control of multiple‐resistant waterhemp population is most likely achieved with two‐pass herbicide programs that include 2,4‐D tank‐mixed with other effective herbicides, such as glufosinate.