Objective To explore the clinical effect of granule fat transplantation in the treatment of upper eyelid depression. Methods A total of 50 patients with upper eyelid depression admitted to the Department of Medical Cosmetology of Liyang Hospital of Traditional Chinese Medicine from February 2021 to February 2023 were selected as the research objects. They were divided into control group and observation group by random number table method, with 25 patients in each group. The control group was treated with orbital septum fat release, and the observation group was treated with granule fat transplantation. The treatment satisfaction, clinical efficacy, pain degree, depression depth and aesthetic improvement score were compared between the two groups. Results The treatment satisfaction of the observation group was 96.00%, which was higher than 76.00% of the control group (P <0.05). The total effective rate of the observation group was 100.00%, which was higher than 68.00% of the control group (P <0.05). The VAS score of the observation group was (3.69±0.27)scores, which was lower than (5.39±0.25)scores of the control group (P <0.05). The depression depth of the observation group was (0.34±0.02)mm, which was lower than that of the control group (0.65±0.01)mm (P <0.05). The aesthetic improvement score of the observation group was (5.67±0.02)scores, which was higher than (3.62±0.03)scores of the control group (P <0.05). Conclusion The clinical effect of granule fat transplantation in the treatment of upper eyelid depression is definite, which can improve the satisfaction of treatment, reduce the VAS score, improve the depth of depression, and improve the aesthetic improvement score. It is worthy of clinical application.