Trained immunity is a rapid innate defense mechanism that enhances the immune system’s overall readiness to deal with various infections. The innate immune system can retain a memory of previous encounters with pathogens or certain stimuli. Beta glucan induced trained immunity was correlated to increased survival during Edwardsiella ictaluri and E. piscicida infections in channel catfish. This study evaluated beta-glucan induced trained immunity on disease resistance to Aeromonas hydrophila and Flavobacterium covae in channel and hybrid catfish. Fish were intraperitoneally (IP) injected with 100 mcg/g body weight beta 1-2 glucan linear structure (Calbiochem, CAS 9012-72-0, derived from Saccharomyces cerevisiae) in 0.8 mL physiological saline. Control fish were IP injected with 0.8 mL physiological saline. Fish were fed 32% protein commercial catfish feed at 3% BW per day. After a 30-day waiting period, anterior kidney tissues from control or beta glucan-exposed fish were dissociated and leukocytes isolated by Histopaque gradient. Leukocytes were incubated with either F. covae or A. hydrophila or physiological saline, and Reactive Oxygen Species (ROS) and Nitric Oxide Synthase (NOS) assays (Invitrogen EEA019 and G7921, respectively) were performed. The adherent cell populations were considered macrophages, and non-adherent cells were considered neutrophils and Natural Killer cells. Significant differences were found in ROS and NOS production of adherent and non-adherent cell populations in hybrid and channel catfish. Trained hybrid macrophages demonstrated significantly higher ROS and NOS values than trained channel catfish macrophages, control hybrid, and control channel catfish macrophages. However, there was no significant difference in NOS between control hybrid macrophages and control channel catfish macrophages. When macrophages from each group were co-incubated with F. covae, only trained hybrid macrophages produced significantly higher NOS values than control hybrid macrophages. Both trained and control hybrid macrophages produced higher ROS and NOS than trained and control channel catfish macrophages, respectively, when co-incubated with F. covae. For the non-adherent cell populations, trained hybrid neutrophils had NOS values significantly higher than trained channel catfish neutrophils, and this significance remained after co-incubation with F. covae. The trained hybrid neutrophils had NOS values significantly higher than the control hybrid neutrophils and they responded to a higher level than the untrained neutrophils after exposure to F. covae. However, this was not observed with the channel catfish. Also, there were no significant differences in the ROS responses of the neutrophils when comparing trained vs untrained before and after bacterial exposure. For the Aeromonas experiment, only hybrid catfish were available. Trained macrophages and neutrophils produced significantly higher amounts of ROS and NOS than control macrophages and neutrophils. Tank survival trials are currently being performed. The current study demonstrated that trained immunity differentially regulates leukocyte responses and disease resistance in hybrid catfish (Ictalurus punctatus x I. furcatus) and channel catfish (I. punctatus). Trained immunity is an exciting and evolving area of immunology and can transform aquaculture to become more efficient and resilient to disease.