Herbicide resistance poses a significant challenge due to the increasing number of weeds resistant to multiple sites of action (SOAs). Recently, smooth pigweed populations resistant to glyphosate have been confirmed in the KwaZulu-Natal Province in the Republic of South Africa (RSA). This study evaluated herbicide products with different SOAs to provide alternative options for controlling glyphosate-resistant (GR) smooth pigweed populations. Dose-response assays for preemergence and postemergence herbicides were conducted under glasshouse conditions at the University of Pretoria, RSA. Seeds of GR smooth pigweed populations from Bergville and Winterton, and a glyphosate-susceptible (GS) population from Hendrina, were used. For the evaluation of preemergence herbicides (mesotrione, atrazine, imazethapyr, and acetochlor), seeds were sown in pots and herbicides were applied 12 hours after sowing. Postemergence herbicides (mesotrione, atrazine, tembotrione and atrazine tank mixture, and chlorimuron-ethyl) were tested on potted plants at the 6-leaf stage. Herbicides were applied at 0×, 0.5×, 1×, 2×, and 4×, where × is the recommended field rate for the herbicide products representing each SOA. Preemergence herbicides provided greater than 90% control across all populations. For postemergence herbicides, mesotrione effectively controlled all the GR populations, whereas the GS population from Hendrina exhibited reduced sensitivity (>50% survival). Atrazine was effective at rates higher than the recommended field rate in the GR populations. The tank mixture of tembotrione and atrazine had an additive effect compared to the sole application of mesotrione and atrazine. Chlorimuron-ethyl was only effective on the GS population. These results suggest that incorporating effective preemergence and postemergence herbicides into weed management programs could improve control of GR populations of smooth pigweed.