Objective To analyze the application effect and safety of autologous fat granule transplantation in minimally invasive plastic surgery of facial depression. Methods A total of 90 patients who underwent facial depression repair in our hospital from October 2022 to October 2023 were selected as the research objects. According to the different surgical methods, they were divided into conventional group (43 patients) and experimental group (47 patients). The conventional group was treated with conventional filling surgery, and the experimental group was treated with autologous fat granule transplantation. The surgical effects and complications of the two groups were compared. Results The morphology of filling area, depression correction effect, expression, adverse reaction score and total score of the experimental group were higher than those of the conventional group, and the differences were statistically significant (P <0.05). The incidence of complications in the experimental group (4.26%) was lower than that in the conventional group (18.60%), and the difference was statistically significant (P <0.05). Conclusion The application of autologous fat granule transplantation in minimally invasive plastic surgery of facial depression can achieve good plastic effect and high safety, which is worthy of clinical application.