Background: Doxorubicin (DOX) is a strong antineoplastic drug that is used for the treatment of several types of cancer and has toxic effects, Annona muricata fruits and leaves possess phytotherapeutic bioactive constituents have potency in the treatment of several diseases. Aim: This study aims to evaluate the therapeutic role of Annona muricata extract (AME) against the testicular damage induced by doxorubicin in male rats. Material &methods: Thirty-two male adult albino rats were used in this study. The rats were divided into four groups (n = 8): the control group, the AME-supplemented group (100 mg/kg b.wt. daily for consecutive 28 days), the DOX-treated group (2 mg/kg twice a week for 4 weeks), and the DOX-treated group that was supplemented with AME. Results: Treatment of male rats with DOX showed a remarkable increase in the levels of serum pro-inflammatory markers, decreased sexual hormones, and decreased testicular antioxidant activities. The treatment of DOX-injected rats with ASE revealed a pronounced return to normalcy of the oxidative stress markers, as evidenced by a remarkable decrease in the testicular MDA and an improvement of SOD, CAT, and GSH activities. On the other hand, the rats administered DOX and AME had considerably decreased serum levels of TNF-α and IL-6 and improved serum FSH, LH, and testosterone levels. AME successfully restored the testicular histopathological signs induced by DOX through amelioration of the architecture of disrupted seminiferous tubules with AME. Conclusion: Annon muricata extract has a potential alleviation role against DOX-induced oxidative stress and inflammation in the testicular tissues.