Although the mechanism of hepatotoxicity from tramadol overdoses is unknown, it is most likelycaused by direct hepatocellular injury, either as a result of ischemia or mitochondrial toxicity. Overdosingon tramadol has been reported to cause acute liver failure. Tramadol-related minor enzyme increases areoften asymptomatic, self-limited, and resolve even when medication is continued. This investigationexamines the short- and long-term effects of tramadol use on liver enzymes in an animal model. The studyinvolved sixty (60) mature Wistar rats of both sexes. Tramadol (300g) were administered to the animals inthe experimental and control groups in the following ways: Before being sacrificed, Group A (n = 5 Malesand 5 Females) received no treatment within the study's time frame. Group B (n = 5 Males and 5 Females)received tramadol 30 mg/kg body weight for 7 days and were sacrificed; Group C (n = 5 Males and 5Females) received tramadol 30 mg/kg body weight for 14 days and were sacrifice; Group D (n = 5 Malesand 5 Females) received tramadol 30 mg/kg body weight for 21 days and were sacrifice, Group E (n = 5Male and 5 Female) received tramadol 30 mg/kg body weight for 42 days and were sacrificed, while GroupF (n = 5 Male and 5 Female) withdrew for 3 weeks after receiving tramadol 30 mg/kg for three weeksbefore sacrificing. Liver was removed from the animals for biochemical examination. The findings of theSPSS analysis on the generated data were expressed as mean SEM. After three and six weeks of tramadoladministration, the results obtained demonstrated a progressive increase in weight and an increase in theactivities of ALT, ALP, and AST in the plasma while decreasing the level of total protein, albumin, directbilirubin as well as indirect bilirubin as compared to the control rats. Therefore, this study comes to theconclusion that tramadol has harmful effects, both acute and chronic, on the structure and operation ofhepatic tissue in wistar rats. As a result, tramadol use needs to be monitored.