Objective To explore the effect of tranexamic acid, glutathione, vitamin C combined with fractional laser on mental state in patients with melasma. Methods A total of 70 patients with melasma admitted to Shanghai Caiting Medical Aesthetic Clinic from May 2022 to June 2024 were selected, and they were divided into the control group and the study group by the random number table method, with 35 patients in each group. The control group was treated with tranexamic acid, glutathione and vitamin C, and the study group was treated with tranexamic acid, glutathione, vitamin C combined with fractional laser. The clinical efffcacy, mental state, adverse reaction rate and satisfaction were compared between the two groups. Results The total effective rate of the study group (94.29%) was higher than that of the control group (82.86%) (P<0.05). The scores of SAS and SDS in the study group after treatment were lower than those in the control group (P<0.05). There was no statistically signiffcant difference in the incidence of adverse reactions between the two groups (P>0.05). The satisfaction rate of the study group (97.14%) was higher than that of the control group (85.71%) (P<0.05). Conclusion The combination of tranexamic acid, glutathione, vitamin C and fractional laser has a good clinical effect in the treatment of melasma. This treatment plan can not only effectively improve skin lesions, but also help to alleviate the negative mental state of patients, with good safety and high patient satisfaction.