This study evaluates the efficacy of antifungal medications for fungal keratitis through a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A comprehensive search of PubMed, Cochrane, and ScienceDirect was performed, including randomized controlled trials (RCT), cohort, and case–control studies on antifungal therapy for fungal keratitis. Keywords and MeSH terms, including “keratitis,” “fungal keratitis,” “antifungal,” and “therapy,” were used to identify relevant studies. The screening process was facilitated through Rayyan, an online-based platform. The inclusion criteria were English-language, full-text human studies on antifungal therapy. Data extraction included study details, interventions, outcomes, and adverse effects, with efficacy evaluated on a scale of 0–2 based on clinical outcomes. Twelve RCT involving 1.715 adult patients from India, China, and Nepal were reviewed. The mean patient age was 48.1 years, with males predominating. All studies used 5% natamycin eye drops, with seven incorporating voriconazole in various forms. Additional therapies included chlorhexidine, amphotericin B, ciprofloxacin, levofloxacin, hypochlorous acid (HOCI), and ketoconazole. Seven studies reported significant improvements in best-corrected visual acuity, infiltrate size, and treatment success. Natamycin monotherapy was shown to have the highest efficacy with a score of 11. Combination therapies, including voriconazole showed effectiveness but with slightly lower scores. In severe cases, combining natamycin with systemic antifungals such as voriconazole, ketoconazole, or amphotericin B was necessary for optimal outcomes. © 2026 Oman Ophthalmic Society.