Edwardsiella piscicida has emerged as one of the most significant bacterial pathogens in U.S. catfish aquaculture, particularly in hybrid catfish (Ictalurus punctatus × I. furcatus), where it causes high mortality in market-sized fish. Diagnostic records from the Aquatic Research and Diagnostic Laboratory (ARDL) in Stoneville, Mississippi, show that hybrids account for roughly half of total disease case submissions but more than 95% of E. piscicida diagnoses. Because hybrids now represent over 50% of U.S. catfish production, E. piscicida poses a potential escalating threat to farm profitability and long-term industry sustainability. To address this challenge, nineteen live-attenuated vaccine (LAV) candidates were developed through serial passage of virulent isolates representing five phyletic groups in increasing concentrations of rifampicin. Screening in hybrid catfish identified five candidates with significant attenuation and strong protection (RPS >70%), and two of the most promising strains, 285R and 346MT, were selected for further evaluation. Both vaccines provided significant protection by oral and immersion routes in channel and hybrid catfish, depending on dose, with greater efficacy observed in hybrids. To improve performance, 285R and 346MT were incorporated into prime-boost vaccination experiments using an experimental Edwardsiella ictaluri (ESC) LAV currently available to producers under veterinary prescription. In these trials, fish were primed orally with either the ESC vaccine or one of the E. piscicida LAVs and boosted 28 days later by immersion or oral delivery of the E. piscicida vaccines. Across combinations, prime-boosted fish exhibited near-complete protection, with relative percent survival ranging from 80–100% following virulent E. piscicida challenge. Importantly, this strategy aligns with current production practices, where first-year fingerlings are already vaccinated against E. ictaluri, a pathogen that primarily affects young fish, while E. piscicida is more prevalent in stocker and market-size fish. Thus, the prime-boost approach has the potential to target both pathogens during the phases of production when they pose the greatest risk. Ongoing work is focused on evaluating and refining booster timing to align with industry practices, dosage, and the use of functional feed additives to enhance oral vaccine performance and protection consistency under production-relevant conditions. Together, these findings validate the protective potential of the 285R and 346MT E. piscicida vaccines and demonstrate the feasibility of integrating them into existing Edwardsiella vaccination programs to reduce antibiotic use, improve fish health, and strengthen the economic sustainability of U.S. catfish aquaculture.