Catfish is one of the most important freshwater fish produced in the United States; however, the production cost of catfish is continuously increasing. To maximize production efficiency and reduce costs, affordable and sustainable alternative protein ingredients are needed. In this study, three commercial animal by-products and soybean meal were tested as protein ingredients to replace fishmeal in catfish fingerling diets. In total, 750 channel catfish juveniles (Ictalurus punctatus) were equally distributed in 25 aquaria, and each tank was assigned one of the five treatment groups [soybean meal (SBM), fishmeal (FM), animal protein concentrates A and B (APC-A/B), and poultry by-product meal (PBM)] (n=5, 30 fish/tank, initial weight = 15.3g). The tanks operated as a recirculating aquaculture system and treatments were distributed in a completely randomized design. Growth performance and water quality were recorded throughout the feeding trial. Fish fed SBM diets demonstrated a significantly lower growth performance and feed efficiency compared to the other groups, and increased intraperitoneal fat and viscerosomatic index compared to the APC-B treatment. Intestinal microbiota presented a higher relative abundance of Pediococcus and Oscillospirales in fish fed the PBM and APC-A diets, respectively. Interestingly, fish receiving APC-A showed the lowest lysozyme activity while fish fed PBM diets had the highest activity. A catfish bacterial pathogen, Edwardsiella ictaluri, was cultured to challenge the remaining fish and assess whether dietary treatments compromised their disease resistance. The PBM had a significantly higher survival after the infection when compared to SBM (PBM: 48.2%, SBM 31.8%). In conclusion, PBM shows promise as an alternative ingredient in catfish diets as it is less expensive when compared to FM, and it does not have deleterious effects but rather promotes antimicrobial activity and survivability after E. ictaluri infection. In comparison, fish fed SBM diets had an increase in visceral fat, reduced growth performance, feed efficiency, and increased disease susceptibility, which are undesirable responses for sustainable aquaculture production.