AbstractControl of waterhemp is becoming more difficult in Ontario because biotypes have evolved resistance to four herbicide sites of action (SOA), including groups 2, 5, 9, and 14. The objective of this study was to compare PRE, POST, and PRE followed by (fb) POST herbicide programs for their effect on control, density, and biomass of multiple-herbicide–resistant (MHR) waterhemp as well as corn injury and grain yield. Two separate field studies, each consisting of five field trials, were conducted over a 2-yr period (2018 and 2019) in fields where corn was grown in Ontario, Canada. The first experiment evaluated MHR waterhemp control with an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) applied PRE, PRE fb glufosinate applied POST, and glufosinate applied POST. The second experiment evaluated MHR waterhemp control with a non-HPPD inhibitor applied PRE, then PRE fb a POST application of atrazine + mesotrione, and then atrazine + mesotrione applied POST. Atrazine + isoxaflutole caused 3% to 5% corn injury at environment 1 (E1); no corn injury was observed with PRE and POST herbicide programs at environments E2, E3, E4, and E5. In general, atrazine/bicyclopyrone/mesotrione/S-metolachlor and dimethenamid-P/saflufenacil applied PRE controlled MHR waterhemp ≥95% 12 wk after POST application (WAA). A POST application of glufosinate following atrazine + tolpyralate PRE, and a POST application of atrazine + mesotrione following atrazine/dicamba or atrazine/S-metolachlor PRE, improved control at 4, 8, and 12 WAA in most environments. In general, PRE fb POST applications resulted in better control of MHR waterhemp throughout the growing season than single PRE and POST applications (P < 0.05). We conclude that herbicide programs based on multiple effective SOAs may offer effective control of MHR waterhemp where field corn is grown. It is advisable that when choosing an herbicide application program that excellent control of MHR waterhemp should be the goal given its high fecundity and competitive ability.