Bacteria are the main cause of diseases in freshwater fish. This study evaluates the antibiogram profile of Proteus mirabilis and its impact on hematology, serum chemistry, and histopathology in African catfish. Agar disc diffusion method was used for antibiogram profile of P. mirabilis. One hundred and sixty Clarias gariepinus juveniles were acclimatized and divided into two groups with four replicates (20 fish per replicate; infected and control group). The fish were infected with P. mirabilis isolates at a rate of 8.5 x 108 CFU/ml by immersion. The control group were not infected. The control and infected groups were observed for 14 days, and mortalities, clinical signs, skin, and gross lesions were recorded. Hematology, histopathology, and blood chemistry were studied. Proteus mirabilis isolates showed multiple drug-resistant characteristics, with a MAR index of 0.60. The mortality rate was 0% and 68.8% in control and infected fish, respectively. Anaemia and lymphocytosis were observed in the infected group. Increased serum globulin, albumin, and total protein were also reported. Moreover, hepatic and renal damage due to high levels of ALT, AST, and creatinine were observed in infected group. The histopathological changes in the skin and kidney section of infected groups showed focal area degeneration in the epidermis, generalized vacuolation of hepatocytes, loose connective tissues in the dermis, renal thrombosis, tubular degeneration, and necrosis of infected fish kidney. Proteus mirabilis was pathogenic and caused organ damages in infected African catfish. Effective biosecurity measures and antimicrobial susceptibility testing before treatment are recommended.