Objective To evaluate the clinical efficacy and safety of 308 excimer light+0.1% tacrolimus ointment in the treatment of vitiligo. Methods A total of 80 patients with vitiligo admitted to Guiping People’s Hospital from January to December 2023 were selected, and they were divided into the control group and the observation group by the random number table method, with 40 patients in each group. The control group was treated with 308 excimer light, and the observation group was treated with 0.1% tacrolimus ointment on the basis of the control group. The clinical efficacy, Vitiligo Area Scoring Index (VASI), Dermatology Life Quality Index (DLQI), T cell subset markers and adverse reactions were compared between the two groups. Results The total clinical effective rate in the observation group was 95.00%, which was higher than 77.50% in the control group (P <0.05). After treatment, the VASI, DLQI, and CD8+ in two groups were lower than those before treatment, while the CD4+/CD8+ and CD4+ were higher than those before treatment. Moreover, the VASI, DLQI, and CD8+ in the observation group were lower than those in the control group, and the CD4+/CD8+ and CD4+ were higher 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 For patients with vitiligo, the application of 308 excimer light+0.1% tacrolimus ointment can improve the clinical efficacy, reduce the severity of vitiligo, improve the quality of life, regulate the expression of T cell subsets, and have good safety.