Objective To explore the effect of collagen combined with cosmetic injection in the treatment of perioral depression and nasolabial folds and its impact on patients' facial aesthetics and skin elasticity. Methods A total of 300 patients with perioral depression and nasolabial folds admitted to the Department of Aesthetic Surgery, Suzhou Lingmei Oriental Medical Beauty Clinic from February 2023 to January 2025 were selected as the research subjects, and they were divided into the control group (n =150) and the observation group (n =150) by the random number table method. The control group was treated with collagen, and the observation group was treated with collagen combined with cosmetic injection. The facial aesthetics, skin elasticity and adverse reactions were compared between the two groups. Results After 3 months of treatment, the scores of facial fullness, appearance aesthetics and skin tightness in 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). After 3 months of treatment, the skin elasticity of corner of mouth, upper and lower lips, and nasolabial fold 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). The incidence of adverse reactions in the observation group was 3.33%, which was lower than 4.00% in the control group, but the difference was not statistically significant (P >0.05). Conclusion Collagen combined with cosmetic injection in the treatment of perioral depression and nasolabial folds can improve patients' facial aesthetics, enhance facial fullness and skin elasticity, and will not increase the incidence of adverse reactions.