Objective To study the clinical efficacy of naftifine hydrochloride and ketoconazole cream in the treatment of Malassezia folliculitis. Methods Fifty patients with Malassezia folliculitis admitted to the People's Hospital of Laibin from April 2020 to December 2021 were selected and divided into control group and observation group according to the random number table method, with 25 patients in each group. The control group was treated with 2% miconazole nitrate cream, and the observation group was treated with naftifine hydrochloride and ketoconazole cream. The clinical efficacy, fungal clearance rate, quality of life and adverse reactions were compared between the two groups. Results The total effective rate of treatment in the observation group was 96.00%, which was higher than 76.00% in the control group (P<0.05). The fungal clearance rate of the observation group was 92.00%, which was higher than 68.00% of the control group (P<0.05). The scores of mental health, social function, general health, physiological function, energy, physical function, emotional function and physiological function in the observation group were higher than those in the control group (P<0.05). The incidence of adverse reactions in the observation group was 8.00%, which was slightly lower than 12.00% in the control group, but the difference was not statistically significant (P>0.05). Conclusion The application of naftifine hydrochloride and ketoconazole cream in the treatment of patients with Malassezia folliculitis can effectively improve the clinical efficacy and fungal clearance rate, improve the quality of life, and do not increase adverse reactions.