Background: Euphorbia heterophylla Linn. is a promising medicinal plant used in traditional medicine for the treatment of constipation, infections, respiratory diseases, skin lesions, malaria, and epilepsy. Objective: This study evaluated the toxicity profile of the aqueous extract of E. heterophylla leaves in female Sprague Dawley rats. Materials and Methods: The toxicity assessment of the aqueous extract of E. heterophylla leaves used the repeated dose 28 and 90-day studies. The rats were orally administered the aqueous extract of E. heterophylla leaves at 50, 100 and 200 mg/kg. The parameters evaluated included body weight gain, haematological and biochemical parameters. Histological sections of organs were also examined. Statistical analysis of results was done using analysis of variance (ANOVA). Results: At the end of the subacute and subchronic toxicity studies, a significant increase (p<0.001, p<0.0001) was observed in the food consumption of rats. Subchronic administration of the extract at 100 and 200 mg/kg significantly decreased (p<0.001, p<0.0001) the body weight of rats at the end of the study. There was also a significant elevation (p<0.05, p<0.01) in aspartate transaminase and platelets, and a significant decrease (p<0.001) in triglycerides. The histology of the liver showed mild clusters of inflammatory cells and cyst observed in the ovarian follicles at 200 mg/kg. Conclusion: The results of this study show some evidence of toxicity in the liver and ovaries on long-term administration of the aqueous extract of E. heterophylla leaves. This suggests need for caution with long-term use of the extract in females. Keywords: Toxicity, Euphorbia heterophylla, Biochemical analysis, Haematological parameters, Sprague Dawley rats.