Field studies were conducted at the Pontotoc Ridge-Flatwoods Branch Experiment Station in Pontotoc, MS in 2015 and 2016 to determine the influence of lay-by metribuzin application on weed control and sweetpotato crop response. With the exception of weedy and hand-weeded checks, all plots received flumioxazin at 107 gaiha−1 pre-transplanting followed by (fb) clomazone at 1,120 gaiha−1 immediately after transplanting. Lay-by treatments consisted of S-metolachlor (800 gaiha−1), metribuzin (210 or 315 gaiha−1), metribuzin (210 gha−1) plus napropamide (1,120 gaiha−1), and metribuzin (210 gha−1) plus S-metolachlor (800 gha−1). At 4 weeks after transplanting, sweetpotato crop injury was 3 to 15%, but was transient and not evident after 6 (2015) to 8 weeks after transplanting (2016). Season-long weed control was excellent (≥98%) for all herbicide treatments used in the study. Hand-weeded check plots yielded 4,600; 18,350; 28,770; and 1,520 kgha−1 of jumbo, No. 1, marketable, and cull grades, respectively. Jumbo, No. 1, and marketable yields from all herbicide-containing treatments in the study were greater than the weedy check and similar to the hand-weeded check. For all treatments, the portion of yield graded as cull was similar to the hand-weeded check. Canner yield response differed between years. In general, canner yield was greater in 2016 (8,460 to 10,670 kgha−1) than 2015 (1,570 to 3,570 kgha−1). In both years, canner yield in all treatments was similar to the hand-weeded check with one exception: in 2015 sweetpotato receiving metribuzin plus napropamide yielded more canners (3,570 kgha−1) than the hand-weeded check (2,300 kgha−1).