Field experiments were conducted in 2016 and 2017 in Champaign County, IL, to study a waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] population (CHR) resistant to 2,4-D and 4-hydroxyphenylpyruvate dioxygenase (HPPD)-, photosystem II–, acetolactate synthase (ALS)-, and protoporphyrinogen oxidase–inhibiting herbicides. Two field experiments were designed to investigate the efficacy of very-long-chain fatty-acid (VLCFA)-inhibiting herbicides, including a comparison of active ingredients at labeled use rates and a rate titration experiment. Amaranthus tuberculatus density and control were evaluated at 28 and 42 d after treatment (DAT). Nonencapsulated acetochlor, alachlor, and pyroxasulfone provided the greatest PRE control of CHR (56% to 75%) at 28 DAT, while metolachlor, S-metolachlor, dimethenamid-P, and encapsulated acetochlor provided less than 27% control. In the rate titration study, nonencapsulated acetochlor controlled CHR more than equivalent field use rates of S-metolachlor. Subsequent dose–response experiments with acetochlor, S-metolachlor, dimethenamid-P, and pyroxasulfone in the greenhouse included three multiple herbicide–resistant (MHR) A. tuberculatus populations: CHR-M6 (progeny generated from CHR), MCR-NH40 (progeny generated from Mclean County, IL), and ACR (Adams County, IL), in comparison with a sensitive population (WUS). Both CHR-M6 and MCR-NH40 are MHR to atrazine and HPPD, and ALS inhibitors and demonstrated higher survival rates (LD50) to S-metolachlor, acetochlor, dimethenamid-P, or pyroxasulfone than ACR (atrazine resistant but HPPD-inhibitor sensitive) and WUS. Based on biomass reduction (GR50), resistant to sensitive (R:S) ratios between CHR-M6 and WUS were 7.5, 6.1, 5.5, and 2.9 for S-metolachlor, acetochlor, dimethenamid-P, and pyroxasulfone, respectively. Values were greater for MCR-NH40 than CHR-M6, and ACR was the most sensitive to all VLCFA inhibitors tested. Complete control of all populations was achieved at or below a field use rate of acetochlor. In summary, field studies demonstrated CHR is not controlled by several VLCFA-inhibiting herbicides. Greenhouse dose–response experiments corroborated field results and generated R:S ratios (LD50) ranging from 4.5 to 64 for CHR-M6 and MCR-NH40 among the four VLCFA-inhibiting herbicides evaluated.