Understanding the interplay between bacterial fitness, antibiotic resistance, host immunity and host metabolism could guide treatment and improve immunity against antibiotic-resistant pathogens. The acquisition of levofloxacin (Lev) resistance affects the fitness of Vibrio alginolyticus in vitro and in vivo. Lev-resistant (Lev-R) V. alginolyticus exhibits slow growth, reduced pathogenicity and greater resistance to killing by the host, Danio rerio (zebrafish), than Lev-sensitive (Lev-S) V. alginolyticus, suggesting that Lev-R V. alginolyticus triggers a weaker innate immune response in D. rerio than Lev-S V. alginolyticus. Differences were detected in the metabolome of D. rerio infected with Lev-S or Lev-R V. alginolyticus. Maltose, a crucial metabolite, is significantly downregulated in D. rerio infected with Lev-R V. alginolyticus, and exogenous maltose enhances the immune response of D. rerio to Lev-R V. alginolyticus, leading to better clearance of the infection. Furthermore, we demonstrate that exogenous maltose stimulates the host production of lysozyme and its binding to Lev-R V. alginolyticus, which depends on bacterial membrane potential. We suggest that exogenous exposure to crucial metabolites could be an effective strategy for treating and/or managing infections with antibiotic-resistant bacteria.