Praziquantel (PZQ) is an acylated quinoline-pyrazine originally developed for veterinary application but now one of the most used anti-helminthic drugs for treatment of certain trematodes and cestodes in both human and other animals. The present study investigated the mutagenic and physiological responses in the juveniles of African catfish, Clarias gariepinus following short term exposure to praziquantel. Based on the 53.52 mg/l 96 h LC50 of PZQ obtained, two sublethal concentrations of 5.35 and 10.70 mg/l of the drug were selected and fish were exposed to these concentrations and control for 15 days. Micronuclei induction in the peripheral blood of PZQ-exposed fish was highest on day 10 but the fish morphological parameters were not affected. The packed cell volume (PCV) was significantly reduced (p<0.05) from day 5 while red blood cells (RBC) and hemoglobin (Hb) significantly declined (p<0.05) on day 15. Macrocytic anemia was observed on day 1 of study and thereafter microcytic anemia developed on day 5 of study. The white blood cell (WBC) was significantly (p<0.05) elevated from day 10 of exposure while values of mean cellular volume (MCV), mean cellular hemoglobin (MCH) and mean cellular hemoglobin concentration (MCHC) were not significantly different (p>0.05) from the control. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glucose levels significantly increased while protein reduced (p<0.05) throughout the exposure period but a mixed trend was observed in the leukocyte differentials. PZQ should be used with caution as sublethal exposure elicited micronucleus induction and alterations of hematological and biochemical parameters in the fish.