Denture-induced stomatitis is the most common pathogenic reaction of denture-bearing mucosa, caused by Candida albicans. Miswak is naturally available oral hygiene tool and have been showed to have antifungal activity against Candida albicans in oral cavity. Aim: The aim of the study was to compare the antifungal efficacy between commercial cleaner (Corega) and Miswak extract ( Salvadora persica) against Candida albicans on heat cured Polymethyl methacrylate (PMMA) acrylic denture base resin. Materials and methods: Forty-eight samples of heat cured PMMA acrylic denture base resin were fabircated in the study. The sterile acrylic resin specimens were immersed in standardized cell suspension of Candida albicans and incubated for 60 min at 370°C for cell adhesion and 2 h at 370°C for biofilm formation. After 24 h biofilm was evaluated by cell viability (CFUs) on SDA and cell counting of Candida albicans under light microscope at 400× magnification. The fungicidal effect of commercial cleaner and Miswak extract on Candida albicans biofilm was then evaluated by colony-forming units on SDA and cell counting under light microscope at 400× magnification. Results: Screening test agar disk-diffusion assay showed mean inhibitory zone of 3 mm for commercial cleaner as compared to Miswak extract, which showed mean inhibitory zone of 2 and 1 mm for different concentrations. Broth microdilution method showed 31 mg/ml MIC and 62.5 mg/ml Minimal Fungicidal Concentration (MFC) values for commercial cleaner as compared to Miswak extract that showed 125 mg/ml MIC and 250 mg/ml MFC values against Candida albicans. A significant difference ( p < 0.05) was observed between pre and post treatment of both commercial cleaner and Miswak extract, for CFUs and cell count for Candida albicans. Conclusion: Commercial denture cleaner (Corega) showed better antifungal ( C albicans) activity than Miswak extract ( Salvadora persica) on heat cured PMMA acrylic denture base resin.