Herbicide-resistant weeds are a growing concern globally; in response, new herbicide resistance traits are being inserted into crops. Isoxaflutole-resistant soybean [Glycine max (L.) Merr.] will provide a new mode of action for use in this crop. Ten experiments were conducted over a 2-yr period (2017, 2018) to determine herbicide interactions between isoxaflutole and metribuzin on soybean injury, weed control efficacy, and soybean yield on a range of soil types. Soybean leaf-bleaching injury caused by isoxaflutole was most severe at sites with higher levels of rainfall after application. Control of weed species with isoxaflutole (52.5, 79, and 105 g ai ha–¹) and metribuzin (210, 315, and 420 g ai ha–¹) differed by site based on amount of rainfall after application. At sites where there was sufficient rainfall for herbicide activation, isoxaflutole at all rates controlled common lambsquarters (Chenopodium album L.), Amaranthus spp., common ragweed (Ambrosia artemisiifolia L.), and velvetleaf (Abutilon theophrasti Medik.) >90%; metribuzin at all rates controlled Amaranthus spp. and witchgrass (Panicum capillare L.) >80%. Control of every weed species evaluated was reduced when there was limited rainfall after herbicide application. The co-application of isoxaflutole + metribuzin resulted in additive or synergistic interactions for the control of C. album, Amaranthus spp., A. artemisiifolia, A. theophrasti, Setaria spp., barnyardgrass [Echinochloa crus-galli (L.) P. Beauv], and P. capillare. Isoxaflutole and metribuzin can be an effective management strategy for common annual broadleaf and grass weeds in Ontario if timely rainfall events occur after herbicide application.