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Effectively treating and preventing outbreaks is crucial for improving the economic benefits of aquaculture. Therefore, utilizing immunostimulants, either alone or in combination, is regarded as a promising strategy. In this study, β-glucan + APS (200 mg/kg + 200 mg/kg), β-glucan (200 mg/kg), APS (200 mg/kg), enrofloxacin (15 mg/kg), and sulfadiazine (15 mg/kg) were added to feed to assess the effects against <i>Nocardia seriolae</i> infection in largemouth bass (<i>Micropterus salmoides</i>) within 14 days. The survival rates did not differ between the enrofloxacin group and the β-glucan + APS group, but both were significantly higher than that of the control group. Additionally, the enrofloxacin group and the β-glucan + APS group exhibited the lowest bacterial loads and tissue damage. Importantly, the β-glucan + APS treatment significantly improved serum enzyme activities (total superoxide dismutase, lysozyme, total protein) and the expression of immune genes (IL-1β, TNF-α, IFN-γ, IgM) compared to the other treatment groups. The enrofloxacin group showed similar efficacy to the β-glucan + APS group in combating <i>N. seriolae</i> infection, but <i>N. seriolae</i> in the enrofloxacin group developed drug resistance. In summary, the combined use of β-glucan and APS is a promising strategy for treating bacterial diseases, thereby contributing to the promotion of sustainable aquaculture development.