As the world population increases and wild caught fisheries decline, aquaculture offers an important sustainable solution in addressing this global challenge. However, disease management remains difficult. With limited options, there is a need for innovative solutions. The cytokine interleukin-22 (IL-22) has emerged as a possible therapeutic target for fish and has been correlated with protection under pathogen challenge. Plant-based production systems have the potential to effectively manufacture and bring unique efficacy-enhancing features to the aquaculture industry; namely, the advantages of low cost for this commodity market, ready scalability, and reduced environmental impact. Plant-expressed recombinant cfIL-22 yield and purity were adequate for in vitro activity assessment. This study serves as the first report supporting the use of plants to express therapeutic proteins with application for the aquaculture industry. Bioactivity assays showed cfIL-22 notably increased the proliferation of catfish cells, highlighting the tissue preservation capabilities of this protein. Recombinant cfIL-22 also upregulated expression of genes encoding a tissue repair protein, fibronectin, an antimicrobial peptide, Natural killer lysin-1, and a common innate immune protein, interferon. These findings support plant-made recombinant catfish interleukin-22 as a potential therapeutic for the aquaculture industry and supports further analysis of this protein for therapeutic use.