Group 3 did not show significant differences in immunoglobulin M (IgM) total levels with an insignificant decrease in phagocytic activity when compared to the control group. All groups showed significant increase in Lysozyme activity. Group 3 did not show significant difference in Alanine aminotransferase (ALT) activity compared to the control group, while group 2 showed the highest values of Aspartate Transaminase (AST) activity than other groups. The highest value of urea was shown in group 2, while there was a decrease in the value of creatinine in the treated groups than the control. Histopathological examination revealed pathological alterations in liver and kidney of the treated groups. After a withdrawal period of 15 days the OTC and FLO residues in O. niloticus muscle were within the permissible limit of Commission Regulation, EU (2010). In conclusion,Florfenicol at 5 mg kg1 body weight is more safe in its effect on Oreochromis niloticus.