Background <p>Radiotherapy is an appropriate treatment for malignancies but can impair antifungal defense, promoting oral candidiasis. <i>Candida tropicalis</i> is of particular concern in immunocompromised patients and its management remains challenging. This study evaluated the antifungal efficacy of <i>Annona muricata</i> and its potential synergistic effect with nystatin against induced oral candidiasis in gamma-irradiated rats.</p> Methods <p>Forty male albino rats were assigned to five groups: R (irradiated), RC (irradiated infected), RCN (treated with nystatin), RCA (treated with <i>A. muricata</i>), and RCNA (treated with both therapies). Antifungal activity against <i>C. tropicalis</i> isolated from human oral lesions was assessed. Infection was introduced on the dorsal tongue surface, and treatment was initiated 48&#xa0;h after inoculation. Rats were sacrificed on days 7 and 10. Body weight, tissue fungal burden, histopathological changes, and scanning electron microscopic findings were evaluated.</p> Results <p><i>A. muricata</i> and nystatin reduced fungal burden and improved mucosal healing, with nystatin performing slightly better as a single treatment. However, their combined use produced the greatest overall improvement in morphology, fungal counts, tissue integrity, and microscopic findings. Untreated infected group showed persistent severe lesions and high fungal load. These results demonstrate a more pronounced effect when both therapies are applied together.</p> Conclusions <p><i>A. muricata</i> may exert antifungal and tissue-protective effects in a gamma-irradiated rat model of oral <i>C. tropicalis</i> infection. Its combination with nystatin may further enhance fungal clearance, improve mucosal integrity, and better maintain body weight compared with either treatment alone.</p>