Eleven field experiments were conducted over a 3-yr period (2010, 2011, and 2012) in conventional- and no-till soybean with a flumioxazin and pyroxasulfone premix. PRE and preplant applications were evaluated for soybean injury, weed control, and yield compared to standard herbicides. Early-season soybean injury from flumioxazin/pyroxasulfone ranged from 1 to 19%; however, by harvest, soybean yields were similar across labeled rates (160 and 200 g ai ha−1), standard treatments, and the nontreated control. Flumioxazin/pyroxasulfone provided excellent control (99 to 100%) of velvetleaf, pigweed species (redroot pigweed and smooth pigweed), and common lambsquarters across almost all rates tested (80 to 480 g ai ha−1). Common ragweed, green foxtail, and giant foxtail control increased with flumioxazin/pyroxasulfone rate. The biologically effective rates varied between tillage systems. The flumioxazin/pyroxasulfone rate required to provide 80% control (R80) of pigweed was 3 and 273 g ai ha−1 under conventional- and no-till, respectively. For common ragweed, the R80 was 158 g ai ha−1 under conventional tillage; yet, under no-till, the rate was nonestimable. The results indicate that flumioxazin/pyroxasulfone can provide effective weed control as a setup for subsequent herbicide applications.