Background: Several reports highlighted the role of nutraceutical compounds in the prevention and management of HPV-related genital lesions both in men and women, with interesting results. Here, we reviewed the effect of ellagic acid and Annona muricata for managing HPV-related genital lesions. Methods: Relevant databases were searched by using methods recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The primary endpoint was the clinical cure, defined as the clinical and/or laboratory and/or histopatologically demonstrated absence of HPV-related lesions at the end of the treatment. Results: We enclosed two retrospective studies, two prospective studies and one randomized controlled trial. In men, ellagic acid and Annona muricata complex improves seminal parameters and HPV-DNA clearance. In women, it has a chemopreventive action in cervical cancer and increases the HPV viral clearance. No clinically significant adverse effects have been reported. Conclusions: In conclusion, the combination of ellagic acid and Annona muricata shows interesting and promising results in terms of HPV viral clearance and HPV related genital lesions. However, more data are necessary to confirm these results.