Menhaden fishmeal (MFM) has a well-balanced amino acid profile and is regarded as the ideal protein source for the majority of aquaculture species. However, the high demand and limited global supply of fishmeal have resulted in consistently high prices, substantially increasing feed costs and subsequently production costs. Animal protein concentrate (APC), is a renderers’ by-product selling for half of the MFM market price. This product has been previously tested and demonstrated to have the potential to completely replace fishmeal. This follow-up study aimed to evaluate the growth performance and disease resistance of channel catfish (Ictalurus punctatus) fingerlings after completely replacing MFM (at 8% inclusion rate) with a commercial APC on a nitrogen or cost-basis (APC at 8 or 16%). A plant-based diet formulated with soybean meal (SBM) was used as a negative control. A total of 840 fish were randomly distributed into 28 aquarium tanks (30 fish/tank, 110-L; n=7) operating as a recirculating aquaculture system, and fish were fed to apparent satiation twice a day for nine weeks. Fish fed APC diets showed significantly greater weight gain and feed efficiency compared to the fish fed the SBM diet. Moreover, dietary inclusion of 16% APC significantly enhanced catfish growth compared to the MFM diet. Preliminary partial budget analysis accounting for growth and feed fed revealed both 8% and 16% of APC diets provided net economic benefits over the MFM diet. The intestinal microbiota was investigated after the feeding trial. Significant differences in beta diversity were observed, with distinct separation of communities between groups fed APC-containing diets and the group offered the plant-based diet. Several taxa at the genus level were identified as have significant differential relative abundance among dietary treatment groups. The remaining fish were challenged with the pathogenic bacteria, Edwardsiella ictaluri. Fish fed 16% APC diet exhibited significantly higher resistance to E. ictaluri compared to the FM group. In conclusion, feeding channel catfish fingerlings with APC can enhance production and health performance, and potentially reduce the production cost or increase revenue with higher growth and survival.