Abstract Background: Annona muricata Linn. (Annonaceae) (AM) fruit juice is widely consumed either raw or after processing in tropical countries because of its very juicy, creamy and sweet character including its medicinal importance. The safety of AM fruit was investigated in Sprague-Dawley rats for acute and 60-day subchronic toxicity effects. Methods: Rats were administered distilled water (DW) and AM daily at doses of 80, 400 and 2000 mg/kg orally for 60 days. At the end of the study, blood samples were assayed for biochemical and hematological parameters. Vital organs were harvested and assessed for antioxidants and histopathology. Results: There was no mortality recorded up to 2000 mg/kg following acute administration. There were no significant changes in vital organ weights and hematological and biochemical parameters. However, significant (p<0.05) reduction in platelet count and packed cell volume was observed at 2000 and 400 mg/kg, respectively, which was reversed after cessation of treatment. Interestingly, subchronic oral administration of AM (80, 400 or 2000 mg/kg) significantly (p<0.001) increased sperm count and motility in comparison to vehicle-treated control. AM long-term treatment induced significant (p<0.05, <0.01 and <0.001) increases in the levels of glutathione, superoxide dismutase (SOD) and catalase, respectively, in the liver and kidney. Conversely, AM (2000 mg/kg) produced significant (p<0.001) increase in malondialdehyde level with decreased (p<0.05) SOD activity in the brain. Conclusions: The study established that AM did not induce any significant toxic effect, indicating that it is safe in rats following oral administration for 60 consecutive days.