Probiotics regulate the health of the host by influencing digestion and absorption, intestinal morphology, microbial composition, and the host's defense against infection. The genus Bacillus encompasses several known probiotics capable of surviving harsh feed processing and extended storage conditions. More importantly, these microbes can still confer probiotic benefits even when administered to animals in the form of spores. Therefore, the screening of Bacillus strains with probiotic potential holds significant importance for aquaculture. In our study, we screened a total of 75 Bacillus strains, leading to the identification of a promising candidate strain, Bacillus velezensis (BSG-2), which has the excellent performance of antagonism towards pathogenic bacteria including Aeromonas hydrophila, Edwardsiella piscicida, and Nocardia seriolae. Genome sequencing provided the evidence of the antibacterial-related genes and gene clusters associated with secondary metabolism. In addition, BSG-2 has a prominent ability to endure harsh environment and secret digestive enzymes, which indicated that BSG-2 has the potential to survive and promote digestion in the intestinal tract through the gastrointestinal tract. Importantly, feeding 56 days, BSG-2 increased activities of digestive and immune-related enzymes, and then promoted growth and decreased mortality and tissue damage of largemouth bass after Nocardia seriolae infection. Collectively, our findings demonstrate that Bacillus velezensis BSG-2 is a promising probiotic candidate offering multiple benefits for largemouth bass.