Japanese foxtail (Alopecurus japonicus Steud.) has developed resistance to multiple post-emergence herbicides in China. Hence, identification of alternative strategies for weed control using pre-emergence herbicides is urgently required. Therefore, we conducted greenhouse dose–response and field experiments over two wheat growing seasons at two sites in Xinyang City (CaiWan and LaoHuShan) to study resistance levels and effective chemical control strategies using the pre-emergence herbicides flufenacet and pyroxasulfone individually and tank-mixed. Greenhouse studies indicated that the CaiWan and LaoHuShan Japanese foxtail populations had a 5.1–35.3-fold resistance to acetyl-CoA carboxylase inhibitors and a 3.7–9.9-fold resistance to acetolactate synthase inhibitors, respectively. Field experiment data analyses revealed that pre-emergence herbicides applied before wheat sowing and immediately after wheat sowing provided >76% weed density and >82% weed biomass control efficiencies 30 and 90 days after sowing, respectively. They showed significantly higher results than herbicides applied after wheat was sown. Compared to the weedy check (control), flufenacet (300 and 450 g/ha), pyroxasulfone (180 and 240 g/ha), and their tank-mix (flufenacet at 300 + pyroxasulfone at 180 g/ha) significantly reduced weed density and biomass (P < 0.05). The tank-mix of flufenacet + pyroxasulfone consistently provided the highest weed control efficiency (85.3–94.5%). The tank-mix applied immediately after sowing resulted in the highest weed control efficiency (88.9–95.6%), the highest wheat yield (5470.3–5527.3 kg/ha), and no observed wheat injuries. However, multiple strategies, such as pre- and post-emergence herbicides, must be adopted to cope with high-density resistant weeds.