Field experiments were conducted in 2010 and 2011 at a Mclean County, IL seed corn production field where resistance to foliar-applied 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors was confirmed in waterhemp. Corn herbicides were applied to the soil at 1 and 2 times (1× and 2×, respectively) the recommended field use rate, while soybean herbicides were applied only at 1× the recommended rate. Waterhemp control and density were determined 30 and 60 d after treatment (DAT). In corn, 1× rates of mesotrione, safened and unsafened isoxaflutole formulations, atrazine, and S-metolachlor provided less than 70% control 30 DAT, while control with acetochlor was greater than 80%. One and 2× rates of acetochlor and 2× rates of mesotrione and unsafened isoxaflutole provided the greatest reduction of waterhemp density across years. At 30 DAT in soybean, sulfentrazone, flumioxazin, metribuzin, and pyroxasulfone provided the highest levels of waterhemp control (84 to 92%), as well as the greatest reduction in waterhemp density both years. A dose–response experiment with soil-applied mesotrione was performed under controlled greenhouse conditions using three waterhemp populations: MCR15 (seed collected from the McLean Co. site), NH41 (progeny obtained from the McLean Co. population by an additional generation of mesotrione selection in the greenhouse), and a sensitive (S). Emergence counts 21 DAT revealed higher seedling survival of MCR15 and NH41 at mesotrione rates of 105 g ha−1 or less compared with the sensitive control. Resistant-to-sensitive (R/S) ratios for NH41 and MCR15 were 12.7 and 8.8, respectively. Field results indicate the McLean Co. waterhemp population demonstrates reduced sensitivity to soil-applied HPPD-inhibiting herbicides. This is supported by greenhouse results that demonstrate reduced sensitivity to mesotrione in MCR15 and NH41.