This study aimed to investigate the efficacy and safety of voriconazole ear drops. A single-center, randomized, double-blind, placebo-controlled clinical design was adopted. A total of 108 patients with otomycosis were enrolled and randomly assigned in a 2:1 ratio to the experimental group (n = 72) and the control group (n = 36). The experimental group received voriconazole ear drops for 7 days followed by placebo for 7 days; the control group received the treatments in reverse order. The primary efficacy endpoint was the clinical response rate. Secondary endpoints included improvement in ear symptoms and signs, and the recurrence rate after discontinuation of treatment. The experimental group showed significant superiority over the control group in the clinical response rate (62.50% vs 38.89%, P < 0.05). Among the secondary endpoints, the improvement rates for ear fullness and ear swelling were significantly higher in the experimental group (P < 0.05), while no significant statistical differences were observed for the other symptoms. The recurrence rate after treatment discontinuation was 7.89%. Regarding safety, no drug-related clinical abnormalities, adverse events, or serious adverse events were observed in any patient. Voriconazole ear drops demonstrated good efficacy and safety in the treatment of otomycosis, showing significant therapeutic effects particularly against filamentous fungal infections. Topical application showed no significant toxicity, indicating promising clinical application prospects.