Background: Various medicinal plants have been studied using modern scientific approaches. These plants have a variety of properties and various biological components that can be used to treat various diseases. However, harmful effects of plants are common clinical occurrence. Objective:This study was designed to investigate toxicological assessment of acute and chronic methanol leaf extract of Vernonia bipontini Vatke (V.bipontini V) on blood, liver and kidney tissues of mice. Methods: Lethal dose (LD) at which 50% of experimental mice died and long term toxicity of methanolic leaf extract of V. bipontini V were determined. Some hematological and biochemical parameters were evaluated. Then, liver and kidney tissues of each animal were taken and processed for light microscopy. Results: Almost all mice treated with 800mg/kg methanol leaf extract of V. bipontini V showed swellings on the left part of abdominal region related to location of spleen, mild diarrhea and enlargement of spleen. The LD50 of the methanol leaf extract of V. bipontini V was 2130.6±1.5mg/kg. Treatment with 800mg/kg body weight of methanol leaf extract significantly decreased body, liver and kidney weights, red blood cells (RBC), haemoglobin (Hgb), mean cell haemoglobin (Mch), Mchc, platelet and significantly increased serum aspartate transferance (AST), vatanine tranferance(ALT) and alkaline phosphate (ALP) levels while 400mg/kg dose had no effect on these parameters. The reduced organ weights did not correlate with loss of body weight at 800mg/kg of methanol leaf extract of the plant. Light microscope observations of liver tissue of mice treated with 800mg/kg of the methanol leaf extract revealed dilated sinusoids, nuclear enlargement, lots of bi-nucleation of hepatocytes, peripheral cramped chromatin, shrinkages (single cell death) of hepatocytes, fragmentation of hepatocytes while no histopathological changes were observed in liver and kidney of mice treated at 400mg/kg. Kidney tissue sections of mice did not show significant histopathological changes at 400mg/kg. However, at 800mg/kg kidney sections showed increased cellularity of glomerulus, urinary space obliteration and enlarged macula densa. Conclusion: This study suggests that the methanol leaf extract may have been phytotoxic to liver that resulted in a rise in serum AST, ALT and ALP levels.