The rise in antifungal resistance among Candida species has prompted the search for alternative therapies, including plant-derived lectins with antimicrobial properties. This study evaluated the antifungal activity of Microgramma vacciniola frond lectin (MvFL) against clinically relevant Candida species and Nakaseomyces glabratus. MvFL exhibited fungistatic activity, with the lowest minimum inhibitory concentrations (MICs) of 0.625 μg/mL for N. glabratus and 1.25 μg/mL for Candida krusei. The minimal fungicidal concentrations (MFC) were not detected, indicating they are above 80 µg/mL. MvFL significantly reduced N. glabratus proliferation, disrupted lysosomal integrity, and affected mitochondrial membrane potential, indicating interference with key cellular processes. MvFL showed minimal activity against biofilm formation, only reducing Candida tropicalis biofilms at a subinhibitory concentration. Combination assays revealed additive or synergistic effects with fluconazole for C. krusei, C. tropicalis, and notably Candida parapsilosis, while antagonism was observed against Candida albicans and N. glabratus. These findings underscore the species-specific nature of lectin-drug interactions and the importance of evaluating such combinations carefully. Overall, MvFL demonstrates significant antifungal potential, particularly as an adjuvant to existing treatments. Its ability to inhibit growth and disrupt cellular function in yeasts supports the development of plant lectins as novel, safer antifungal agents in response to the growing challenge of antifungal resistance.