Objective To investigate the application effect of oxymetazoline hydrochloride combined with tacrolimus in patients with persistent facial erythema associated with rosacea. Methods A total of 80 patients with persistent facial erythema associated with rosacea admitted to our hospital from March to December 2022 were selected as the research objects. They were divided into control group and observation group by random number table method, with 40 patients in each group. The control group was treated with 0.1% tacrolimus ointment, and the observation group was treated with oxymetazoline hydrochloride combined with tacrolimus. The clinical efficacy, improvement time of clinical symptoms, skin barrier function indexes and adverse reactions were compared between the two groups. Results The total effective rate of treatment in the observation group was 92.50%, which was higher than 72.50% in the control group (P<0.05). The improvement time of skin flushing, telangiectasia and erythema in the observation group were shorter than those in the control group (P<0.05). After 30 days of treatment, the transcutaneous water loss (TEWL) and facial erythema in the observation group were lower than those in the control group (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion The application of oxymetazoline hydrochloride combined with tacrolimus in patients with persistent facial erythema associated with rosacea is effective, which can improve the therapeutic effect, shorten the improvement time of clinical symptoms, improve the skin function of patients. At the same time, the combined treatment does not increase the incidence of adverse reactions, and the application safety is high