Background Phyto-medicine represents a vast pool of novel drug development, but understanding their safety requires elaborate, multifaceted approaches, including toxicity studies. Objective This study investigated the effects of 90 days of oral administration of Datura stramonium (DSE) leaf extract in Rats. Methods In the oral acute toxicity study, mice were treated with a single oral gavage of DSE at 500, 1000, and 2000 mg·kg-1/d, po and observed for signs of acute toxicity for 14 days. In the sub-chronic study, rats were randomized into four Groups (A–D). Group A received distilled water (10 mL·kg-1, po) while groups B–D received DSE (10, 50 and 250 mg·kg-1/d, po, respectively) orally for 90 days uninterrupted. Animals were weighed weekly, with food and water measured daily and relevant parameters assayed at the end of the 90days administration. Results In acute toxicity studies, oral administration of up to 2 g·kg-1/d, po of DSE did not elicit any semblance of toxicity or mortality within 24 h to 14 days. In the 90days studies, DSE (250 mg·kg-1/d, po) decreased the body weight, brain weight, and food intake in female rats. DSE (10–250 mg·kg-1/d, po) increased the red blood cell (RBC), packed cell volume (PCV) and hemoglobin (Hb) in both sexes. DSE (10–250 mg·kg-1/d, po) increased the triglycerides (TG), cholesterol and low-density lipoprotein (LDL); and decreased HDL in both sexes. DSE (10–250 mg·kg-1/d, po) increased the white blood cells (WBC) and platelets in female rats. DSE (10–250 mg·kg-1/d, po) decreased the alkaline phosphatase (ALP) and alanine transaminase (ALT) in both studies. Serum urea level was decreased in both sexes. DSE (250 mg·kg-1/d, po) decreased male rats' serum sodium ion levels. Liver, brain, testes and kidney showed severe lesions at 250 mg·kg-1/d, po of the extract. Conclusion D. stramonium is safe on acute exposure and relatively safe on sub-chronic oral administration. However, prolonged use, especially at high doses, could cause Liver, brain and kidney toxicities; and abnormal lipid metabolism.