Background In recent years, autologous fat grafting (AFG), also known as fat transfer or lipofilling, has been widely performed for periorbital rejuvenation and defect correction, although the evidence regarding its efficacy and safety is still lacking. Besides, with respect to the periorbital region, it is invariably the earliest appearance area of the facial aging phenomenon. Therefore, a systematic review and meta-analysis is needed to evaluate the efficacy and safety of this technique. Methods A literature search was performed in PubMed, Embase, and the Cochrane library databases on November 20, 2020, adhering to the PRISMA guidelines, to identify all relevant articles. Then, a data extraction and standardization process was performed to assess all outcome data. Ultimately, the data were assessed using a random effects regression model with comprehensive meta-analysis software. Results Thirty-nine studies consisting of 3 cohorts and 36 case series with a total of 4046 cases were included. Meta-analysis revealed a relatively high satisfaction rate of 90.9% (95% CI, 86.4%-94.0%). Frequent complications in 4046 patients receiving AFG were edema, chemosis, and contour irregularity, with an overall complication rate of 7.9% (95% CI, 4.8%-12.8%). Conclusion This systematic review and meta-analysis showed that AFG for rejuvenation of eyelids and periorbital area provided a high satisfaction rate and did not result in severe complications. Therefore, AFG might be performed safely for periorbital rejuvenation and reconstruction.