INTRODUCTION: due to the fact that antimicrobial peptides antimicrobial peptides (AMPs) from climbing perch have not been fully explored for their antimicrobial potency, this investigation was undertaken to explore that possibility. METHODS: antimicrobial peptides (AMPs) from the mucous secretion of climbing perch were obtained and an in-vivo analysis was conducted using mice. RESULTS: the results showed inhibitory effects on multidrug-resistant multidrug-resistant Pseudomonas aeruginosa with reduced mortality from 100% among the non-treated group to 25%. Similarly, the level of serum transaminase enzymes (AST and ALT), creatinine levels, and pro-inflammatory cytokines (TNF-α and IL-6) were all found to be higher in the non-treatment group compared to the AMP-treatment group. Also, extensive tissue damage in the lung, liver, and spleen of the non-treated control group mice was observed based on the histopathological lesions recorded. As expected, AMPs from climbing perch significantly alleviated multidrug-resistant P. aeruginosa infection in-vivo and produced enhanced therapeutic efficacy superior to the ciprofloxacin treatment. CONCLUSION: this study provides insight into the potential antimicrobial activity of fish innate immune system-derived peptides that could serve as a candidate for the substitute of antibiotics.