Objective To analyze the effect of fractional CO2 laser treatment on skin physiological indicators and serological indicators in patients with rosacea. Methods A total of 88 patients with rosacea admitted to Bao'an District Traditional Chinese Medicine Hospital from January 2024 to January 2025 were selected as the research subjects, and they were divided into the control group and the observation group by the random number table method, with 44 patients in each group. The control group was treated with hydroxychloroquine sulfate tablets alone, and the observation group was treated with fractional CO2 laser combined with the same tablets. The skin physiological indicators, serological indicators, erythema improvement effect, quality of life and clinical efficacy were compared between the two groups. Results At 12 weeks after treatment, the sebum content and epidermal water content in the observation group were higher than those in the control group, and the transepidermal water loss was lower than that in the control group (P <0.05). At 12 weeks after treatment, the contents of T, TNF-α and IL-8 in the observation group were lower than those in the control group (P <0.05). At 6 and 12 weeks after treatment, the CEA score and DLQI score in the observation group were lower than those in the control group (P <0.05). The total effective rate of treatment in the observation group (97.73%) was higher than that in the control group (84.09%) (P <0.05). Conclusion Fractional CO2 laser has an ideal clinical effect in the treatment of rosacea, which can improve skin barrier function and erythema symptoms, enhance patients' quality of life, and reduce inflammatory response. It is worthy of clinical application.