Burn injuries in the United States result in 1.1 million hospital admissions, with around 4500 deaths annually, according to the CDC. Although skin grafts have been the standard treatment since 1869, recent research suggests that tilapia skin could offer a safer and more effective alternative. This review aims to assess the strengths and knowledge gaps related to the usage of fish skin in burn patients. A systematic search was conducted on electronic databases, such as PubMed, Scopus, Web of Science, Clinicaltrials.gov, and Google Scholar, using relevant MESH keywords from 2018 to 2022. The search and analysis followed the “Preferred Reporting Items for Systematic Reviews and Meta-analysis” methodology. Data extraction utilized a template based on the Cochrane Consumers and Communication Review group’s extraction guidelines. Out of 166 studies identified, 12 relevant studies were extensively analyzed. The trials consistently demonstrated accelerated reepithelialization, improved patient compliance in managing burn-related pain, no immunologic or allergic reactions, reduced infection rates, shorter hospital stays, and decreased treatment costs when using fish skin. These findings suggest that fish skin is comparable to traditional treatments in terms of effectiveness and safety. Considering the discussed advantages, Nile tilapia fish skin emerges as a promising xenograft option for burn victims. However, further large-scale trials and studies are needed before its widespread and official implementation in burn centers. More research is required to establish the efficacy and safety of fish skin as a viable treatment modality.