Citrullus lanatus (watermelon) seed oil is one of the neglected and underutilized seed oils in Nigeria. This study was aimed at evaluating the therapeutic efficacy of crude and degummed Citrullus lanatus seed oil (CLSO) in the treatment of experimental oral candidiasis induced by Candida albicans in immunosuppressed female albino rats. In vivo antifungal activity of the extracts was analyzed by microbiological and histopathological analyses, along with renal function tests at days 7 and 14 post infection treatments. The observations in the test animal groups were compared with that of control group treated with fluconazole. Treatments with CLSO resulted in significant body weight loss. Also, there was a significant reduction in the kidney fungal burden (cfu/ml/g) of rats treated with CLSO after fourteen days post infection treatment, compared to group 3 (untreated control) rats. Histologically, group 3 (untreated) showed multifocal aggregation and widespread distribution of fungal blastospores appearing singly or in small clusters within the renal parenchyma when compared with CLSO-treated groups, which had minimal fungal blastospores that appeared singly in the renal tissues. Thus, histological data were corroborated with microbiological tests for crude and degummed CLSO, but not for the fluconazole-treated group which showed multifocal and widespread distribution of blastospores at day 14. Furthermore, within the CLSO treatment group, a significant increase in the (plasma) levels of creatinine was observed, while no significant difference in blood urea values was recorded after day 14 post infection study. Histopathological alterations in the kidney was restored to normal. CLSO could be considered as a potential antifungal agent especially the degummed CLSO and could also be employed in the management of weight loss.