Objective To explore the effect of azelaic acid cream combined with tranexamic acid on pigmentation index and skin glossiness in patients with melasma. Methods A total of 80 patients diagnosed with melasma in the Department of Skin Cosmetology, Chenzhou 3rd People's Hospital from February 2024 to February 2025 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 tranexamic acid tablets, and the observation group was treated with azelaic acid cream combined with tranexamic acid. The pigmentation index, skin glossiness, blood indicators, quality of life and adverse reaction rate were compared between the two groups. Results After 8 weeks of treatment, the pigmentation index and skin glossiness of the two groups were better than those before treatment, and those of the observation group were better than those of the control group (P<0.05). After 8 weeks of treatment, the levels of cyclooxygenase and melanocyte-stimulating hormone in the two groups were lower than those before treatment, and those in the observation group were lower than those in the control group (P<0.05). After 8 weeks of treatment, the level of vascular endothelial growth factor in the two groups was higher than that before treatment, and that in the observation group was higher than that in the control group (P<0.05). After 8 weeks of treatment, the scores of each dimension of quality of lifein the two groups were higher than those before treatment, and those 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 5.00%, which was lower than 7.50% in the control group, but the difference was not statistically signiffcant (P>0.05). Conclusion The combined treatment of azelaic acid cream and tranexamic acid has a good effect in patients with melasma. It can effectively reduce skin pigmentation, improve skin glossiness, optimize serum indicators, and enhance patients' quality of life, and does not increase the risk of adverse reactions.