Objective To investigate the efficacy and safety of enhanced recovery after surgery (ERAS) in the perioperative period of pancreaticoduodenectomy (PD). Methods Chinese and English databases were searched for controlled clinical trials on the application of ERAS in PD published from 2000 to 2021. Screening, quality assessment, and data extraction were performed for the articles, and RevMan5.3 software was used for meta-analysis. This study was registered on PROSPERO with a registration number of CRD42021287931. Results A total of 22 controlled clinical trials were included, with 3531 patients in total. The results showed that the implementation of ERAS in the perioperative period of PD reduced the incidence rates of total complications (odds ratio [ OR ]=0.63, 95% confidence interval [ CI ]: 0.48-0.83, P =0.001), abdominal infection ( OR =0.65, 95% CI : 0.47-0.88, P =0.005), pulmonary complications ( OR =0.57, 95% CI : 0.42-0.78, P =0.000 5), pancreatic leakage ( OR =0.80, 95% CI : 0.67-0.97, P =0.02), and delayed gastric emptying ( OR =0.58, 95% CI : 0.48-0.71, P < 0.001) and effectively shortened the length of postoperative hospital stay (mean difference=-2.76, 95% CI : -3.36 to -2.16, P < 0.001). However, there were no significant differences between the two groups in mortality rate, incision infection, postoperative bleeding rate, reoperation, and rehospitalization (all P > 0.05). Conclusion ERAS has good efficacy and safety in the perioperative period of PD and can significantly reduce the incidence rates of postoperative complications and shorten the length of postoperative hospital stay. Therefore, it holds promise for clinical application.