The present study was carried out to investigate the efficacy of propolis and norfloxacin against Aeromonas hydrophila in Nile catfish (Clarias garipeinus). Fish were collected from a private fish farm in Sharkia Governorate and fed commercial fish diet. Fish were divided into six groups; Group 1: non-infected non-treated, Group 2: experimentally infected with A. hydrophila and non-treated, Group 3: normal fish administered propolis in feed by dose (10g/kg BW for 10 days), Group 4: infected fish treated with therapeutic dose of norfloxacin (10mg/kg BW for 10 days), Group 5: infected fish treated with propolis and Group 6: infected fish treated with therapeutic dose of norfloxacin and propolis (with the previous dose). The results indicated that propolis and norfloxacin were effective against A. hydrophila. The hematological parameters were improved in Groups 4, 5 and 6 when compared with Group 2. The second group showed a significant increase (p < 0.05) in serum aspartate aminotransferase (AST), alanine aminotransferrase (ALT), urea, creatinine and malondialdhyde activity, while the mentioned parameters were improved decreased in Groups 5 and 6. Also, our results revealed a significant increase (p < 0.05) in immunological parameters in Groups 3, 5 and 6. Moreover, this study also reported the pathological lesions in gills, liver, kidneys, heart, spleen and intestine of fish infected with A. hydrophila which became milder in treated fish especially with propolis and antibiotic. The present results suggest that the administration of propolis and norfloxacin were effective against A. hydrophila without hazard effects on hematological and biochemical parameters.