Late-season escapes of Palmer amaranth and waterhemp (collectively referred to as Amaranthus spp.) pose a significant challenge in cotton production due to their high fecundity, herbicide resistance, and ability to replenish the weed seedbank at harvest. While harvest weed seed control (HWSC) has been adopted in grain systems, its feasibility in cotton remains unknown due to differences in cotton harvesting equipment design. Therefore, this study aimed to determine the fate of Amaranthus spp. seeds during harvest with cotton picker and stripper harvesters, and evaluated the efficacy of an impact mill to destroy a range of weed seeds present in different cotton debris types. Along with the seed cotton, cotton strippers removed 52% of the Amaranthus spp. seeds, compared to just 7% for pickers, which then get cleaned at the cotton gin. About 85% of the seeds were retained on the plant after harvest by the pickers, and about 15% by the strippers. Seeds shattered to the ground accounted for 8% with pickers and 18% with strippers. Additionally, the cotton stripper’s field cleaner mechanism removed 15% of the weed seeds. Together, seeds collected in seed cotton, retained on the plant, or separated by field cleaners (in strippers) represent points for HWSC implementation. Different types of cotton debris were then run through a stationary weed-seed impact mill with a known number of seeds for seven weed species to determine seed destruction efficacy. The stem debris had a 29% moisture content, which is too high for the impact mill and caused mill clogging; however, seed kill levels of 98% were achieved in bur debris and gin debris types, values similar to those reported in grain systems. Together, these findings provide a framework for incorporating HWSC practices into cotton, offering growers and processors a way to reduce weed seedbank inputs.