Objective. This retrospective study evaluates the efficacy of acellular fish skin graft for the treatment of full-thickness diabetic foot ulcers (DFUs). The primary objective is to calculate the total wound surface area (cm2) healed over a 16-week period. The secondary objective is to provide a systematic review on acellular fish skin grafts. Materials and Methods. There were 51 patients with a total of 58 DFUs treated with an acellular fish skin graft by the principal investigator. The initial wound surface area at first application was compared with the final wound surface area to conclude the percentage of total wound healed over a 16-week treatment period. Results. At 16 weeks, there was a mean reduction of wound surface area by 87.57% and 35 wounds (60.34%) fully healed. The systematic literature review included 10 fish graft articles, 3 of which specifically evaluated lower extremity ulcers. The reviewed studies supported improved wound healing with fish graft application, with benefits noted in dentistry, neurology, and wound care. Conclusions. This retrospective study further supports previous evidence that acellular fish skin graft promotes wound healing in DFUs. In particular, a rapid increase in wound healing was observed during the initial 4 weeks following graft application. This study and review of the literature indicated that fish graft encourages wound healing by enabling the wound to transition from a chronic to an acute stage of healing.