Due to depressed corn and soybean prices over the last few years in the United States, growers in Nebraska are showing interest in no-tillage (hereafter referred to as no-till) conventional (non–genetically engineered [non-GE]) soybean production. Due to the increasing number of herbicide-resistant weeds in the United States, weed control in no-till non-GE soybean using POST herbicides is a challenge. The objectives of this study were to compare PRE-only, PRE followed by (fb) POST, and PRE fb POST with residual (POST-WR) herbicide programs for Palmer amaranth and velvetleaf control and soybean injury and yield, as well as to estimate the gross profit margins and benefit–cost ratio of herbicide programs. A field experiment was conducted in 2016 and 2017 at Clay Center, NE. The PRE herbicides tested in this study resulted in ≥95% Palmer amaranth and velvetleaf control at 28 d after PRE (DAPRE). Averaged across the programs, the PRE-only program controlled Palmer amaranth 66%, whereas 86% and 97% control was obtained with the PRE fb POST and PRE fb POST-WR programs, respectively, at 28 d after POST (DAPOST). At 28 DAPOST, the PRE fb POST herbicide programs controlled velvetleaf 94%, whereas the PRE-only program resulted in 85% control. Mixing soil-residual herbicides with foliar-active POST programs did not improve velvetleaf control. Averaged across herbicide programs, PRE fb POST programs increased soybean yield by 10% and 41% in 2016 and 2017, respectively, over the PRE-only programs. Moreover, PRE fb POST-WR programs produced 7% and 40% higher soybean yield in 2016 and 2017, respectively, compared with the PRE fb POST programs. The gross profit margin (US$1,184.3 ha−1) was highest under flumioxazin/pyroxasulfone (PRE) fb fluthiacet-methyl plus S-metolachlor/fomesafen (POST-WR) treatment; however, the benefit–cost ratio was highest (6.1) with the PRE-only program of flumioxazin/chlorimuron-ethyl.