Citrus processing sector generates tremendous amounts of by-product that contains variety of bioactive compounds such as phytochemicals, including flavonoids, carotenoids, apocarotenoids, terpenes, limonoids, and other health-promoting nutrients. However, many bioactive compounds in plant cells need to be bioaccessible and bioavailable to have any beneficial effects to the host. To enhance bioavailability of bioactive compounds, two types of citrus pulps (orange and lemon pulp) were modified by processing with either thermochemical or supermasscolloidization techniques. This study was conducted to determine the protective effect of dietary supplementation of modified citrus pulp against virulent Aeromonas hydrophila, one of the most economically important bacterial diseases affecting the channel catfish, Ictalurus punctatus industry in the United States. A 10-week study was conducted to evaluate the effect of dietary supplementation (2%) of lemon pulp or orange pulp. The study evaluated the results of two different techniques as well as the unprocessed form on growth, feed utilization, body proximate composition, hematology, serum biochemistry, immune responses and disease resistance of channel catfish (11.36 ± 0.09 g) in triplicate aquaria fed to apparent satiation twice daily. Fish fed diets supplemented with modified orange pulp treated with either thermochemical or supermasscolloidization and lemon pulp that received thermochemical treatment had significantly better survival rate against A. hydrophile challenge than fish fed either untreated citrus pulp or the control (not supplemented) without any negative effect on fish performance. Supplementation of both modified orange pulp significantly increased complement activity of fish compared to fish fed untreated orange pulp or control diet. However, fish fed lemon pulp that received supermasscolloidization had significantly lower weight gain, feed intake, and hematological values than fish fed control diet. Dietary supplementation of modified citrus processing waste, orange waste in particular, in aquafeeds may prove cost effective and beneficial in increasing resistance of channel catfish against bacterial infection.