Objective To investigate the clinical effect of tacrolimus ointment combined with minocycline hydrochloride in the treatment of rosacea. Methods A total of 60 patients with rosacea who were treated in our hospital from January to December 2021 were selected as the research objects. They were divided into observation group and control group by random number table method, with 30 patients in each group. The control group was treated with minocycline hydrochloride capsules orally, and the observation group was treated with tacrolimus ointment on the basis of the control group. The skin lesions, subjective symptoms, clinical efficacy and incidence of adverse reactions were compared between the two groups. Results The mild proportion of the observation group after treatment was higher than that of the control group, and the difference was statistically significant (P<0.05). After treatment, the symptom scores of the observation group were lower than those of the control group, and the difference was statistically significant (P<0.05). The total effective rate of the observation group was higher than that of the control group, and the difference was statistically significant (P<0.05). The incidence of adverse reactions in the observation group was higher than that in the control group, but the difference was not statistically significant (P>0.05). Conclusion Tacrolimus ointment combined with minocycline hydrochloride in the treatment of rosacea can achieve better therapeutic effect, improve the clinical symptoms, and has high safety, which is worthy of clinical application.