Cissampelos pareira Linn has been used traditionally in the management of several diseases including diabetes mellitus but its efficacy and safety after long term use is not scientifically evaluated. The aim of this study was to determine in vivo hypoglycemic activity and safety of aqueous leaf extracts of C. pareira in white male albino rats. The extracts were screened for their hypoglycemic activity in alloxan induced diabetic rats using the oral and intraperitoneal routes. The safety of these extracts was studied in rats orally or intraperitoneally administered with 1 g/kg body weight daily for 28 days by recording the changes in body and organ weight, hematological and biochemical parameters and histology. Mineral composition of the extracts were estimated using total reflection X-ray fluorescence system (TRXF) while the types and quantities of phytochemicals present were assessed using standard procedures. Aqueous extracts orally and intraperitoneally administered at 50 mg/kg, 100 mg/kg and 150 mg/kg body weight demonstrated hypoglycemic activity with the intraperitoneal route being more effective than the oral route. Oral and intraperitoneal dose of 1 g/kg body weight of the leaf extracts significantly reduced the body weight gain. The same intraperitoneal dose increased the liver and spleen, and decreased the testis weight; and reduced the hemoglobin levels, packed cell volume and increased the platelet count; increased the activity of aspartate aminotransferase, and lactate dehydrogenase, and decreased the activity of alkaline phosphatase, γ-glutamyltransferase, and creatine kinase and histologically slightly injured the liver and spleen and orally increased the activity of alanine aminotransferase, lactate dehydrogenase, and creatine kinase, and decreased the activity of aspartate aminotransferase and γ-glutamyltransferase. The extracts contained phenols, tannins, flavonoids, alkaloids, terpenoids, sterols, and reducing sugars. Potassium, calcium, and iron levels in the extracts were below the recommended daily allowance. In conclusion, the observed hypoglycemic activity and slight toxicity could be associated with the phytonutrients present in this plant extract. This study recommends continued use of this plant as an herbal medicine.