Background and Purpose: Synsepalum dulcificum (Sapotaceae) is used in traditional medicine for treatment of diabetes, cough and cancer. This study was designed to investigate the in vivo toxicological endpoints of the ethanol leaf extract of S. dulcificum in male and female rats. Methods: After estimating the LD50 in mice, forty-eight rats were randomly assigned to four groups of twelve rats each in a sex ratio of 1:1 and were orally administered 10 mL/kg distilled water (control) and 118, 237, 475 mg/kg/day of the extract respectively for forty-five days. The animals were thereafter euthanized and blood samples collected for haematological, biochemical and antioxidant assays. Sperm parameters were evaluated and testis, liver, heart and ovary were harvested for histopathology. Constituents of the extract were determined by GC-MS. Result: The LD50 (oral) was estimated to be 4750 mg/kg in mice. There was a significant decrease in haemoglobin but lymphocytes and monocytes were significantly increased compared to control. Aspartate transaminase and alanine transaminase were significantly increased compared to control. Creatinine increased, high density lipoprotein (HDL) and albumin decreased significantly in treated rats. There was a significant increase in enzymatic and non-enzymatic antioxidants and a significant reduction in malondialdehyde (MDA). There were significant increases in reproductive markers of sperm count, motility and abnormality. Renovascular congestion and preserved cytoarchitecture in other organs were observed. Twenty-one compounds including n-hexadecanoic acid, oleic acid, 2,3-dihydro-3,5-dihydroxyl-6- methyl-4H-pyran-4-one (DDMP) and phytol were identified. Conclusion: Prolonged use of the ethanol leaf extract of S. dulcificum could result in hepatic and renal dysfunctions and may increase the risk for male infertility and cardiovascular diseases.