Tiafenacil is a recently developed protoporphyrinogen IX oxidase (PPO)-inhibiting herbicide from the pyrimidinedione chemical class that is proposed for use as a preplant (PP) burndown in soybean. Glyphosate-resistant (GR) horseweed is a troublesome weed often found in no-till systems that can dramatically reduce soybean yield; control in soybean has been variable. Five field experiments were conducted over 2019 and 2020 in commercial soybean fields with GR horseweed to determine the biologically effective dose (BED) of tiafenacil and tiafenacil + metribuzin and to compare their efficacy to currently accepted industry standard herbicide treatments in identity-preserved (IP, non-GMO), GR, and glyphosate/dicamba-resistant (GDR) soybean systems. There was no soybean injury with treatments evaluated. The calculated doses of tiafenacil for 50%, 80%, and 95% control of GR horseweed control were 21, 147, and >200 g ai ha−1, respectively, at 8 wk after application (WAA). Lower doses were calculated with the addition of metribuzin (400 g ai ha−1) to tiafenacil for 50% and 80% control, with no dose of tiafenacil + metribuzin providing 95% control. Tiafenacil + metribuzin at 25 + 400 and 50 + 400 g ai ha−1 controlled GR horseweed 88% and 93%, respectively, which was similar to the industry standards of saflufenacil + metribuzin (25 + 400 g ai ha−1) and glyphosate/dicamba + saflufenacil (1,200/600 + 25 g ai ha−1) that provided 98% and 100% control, respectively, at 8 WAA. This study presents the potential utility of tiafenacil + metribuzin as a GR horseweed management strategy in soybean.