Background: The growing appropriateness of the use of herbal preparations in the treatment of countless diseases must be thoroughly accompanied by the evaluation of the safety of these remedies. Despite the availability of known antidiabetic medicine in the pharmaceutical market, diabetes and the related complications continue to be a major medical problem. Objective: The objective of this study was to evaluate the toxicological effects of the methanolic leaf extract of Piliostigma reticulatum (DC) Hochs in male Wistar rats. Materials and Methods: This evaluation was carried out both in vitro and in vivo. In vitro, acute toxicity test was evaluated according to Lorke’s method. This method was carried out in two phases. In the first phase, the rats were grouped into three with three rats in each group and administered 10 mg/kg, 100 mg/kg and 1000 mg/kg of the extract. In the second phase, the rats were also grouped into three and administered 1600 mg/kg, 2900 mg/kg and 5000 mg/kg. The extract at a single dose of 5000 mg/kg showed no signs of toxicity nor mortality in any of the animals tested during 7 day observation period.Liver function test was also evaluated in this study. The rats were grouped into nine made up of fifteen rats each and were administered the methanolic leaf extract of Piliostigma reticulatum (DC) Hochst for 14 days. The serum levels of alanine and aspartate transaminases (ALT and AST), alkaline phosphatase (ALP) were carried out. Results: Results from the in vitro toxicological evaluation reveals that the LD 50 is greater than 5000 mg/kg according to Lorke’s method. There was no death recorded, neither was there any convulsion, salivation or a change in the skin color recorded. Also, the liver function tests carried out revealed a significant (p<0.0001) increase in the activities of Alanine (ALT), Aspartate transaminases (AST) and alkaline phosphatase (ALP) enzymes compared to the negative control rats. This indicates that there was a problem with liver function. Treatment with the methanolic leaf extract of Piliostigma reticulatum (DC) Hochstand gilbenclamide significantly (p<0.0001) reduced the activities of AST, ALT and ALP and ameliorated the alteration in liver function. Treatment with extracts alone (without diabetes) did not have any significant effect on AST, ALT and ALP compared with the negative control rats. Conclusion: The findings in this study revealed that the methanol leaf extract of Piliostigma reticulatum (DC) Host does possess properties that reverse hepatocellular damage in rats. Toxicological evaluation carried out showed no mortalities or adverse clinical manifestations. The biochemical analysis also revealed that the plant is considered very safe up to 5000 mg/kg. This extract is however recommended to cure damage that may have taken place in the liver.