Background Regenerative techniques are increasingly applied in endodontic surgery, but different materials used in regenerative techniques may have varying impacts on wound healing. Objectives This study evaluated the effects of different regenerative techniques and materials on the outcome of endodontic surgery. Participants: patients with persistent periapical lesions, treated with root‐end surgery. Control: endodontic surgery without the use of regenerative techniques/materials. Intervention: endodontic surgery with the use of regenerative techniques/materials. Outcome: combined clinical and radiographic results. Methods PubMed, Web of Science, Embase, SinoMed and the CENTRAL Cochrane were searched up to 10th July 2020, followed by a manual search. Detailed eligibility criteria were applied. Cochrane’s risk‐of‐bias tool 2.0 was used to assess the risk of bias of the eligible studies. Meta‐analysis was conducted using RevMan software. Subgroup analyses were performed based on the regenerative materials used in endodontic surgery. Results Eleven eligible randomized controlled trials (RCTs) were included in the meta‐analysis: two had a low risk of overall bias, and nine had some concerns of overall bias. Generally, the use of regenerative techniques significantly improved the outcome of endodontic surgery (risk ratio [RR]: 0.42; 95% confidence interval [CI], 0.26–0.68; P < 0.001). On subgroup analysis, the use of expanded polytetrafluoroethylene (e‐PTFE) membranes alone had no added benefits (RR: 2.00; 95% CI, 0.22–18.33; P = 0.54). The application of collagen membranes or autologous platelet concentrates (APCs) alone was associated with a trend for better outcomes (RR: 0.51; 95% CI, 0.20–1.25; P = 0.14) (RR: 0.55; 95% CI, 0.18–1.71; P = 0.30). The combined use of collagen membranes and bovine‐derived hydroxyapatite significantly improved the outcome (RR: 0.35; 95% CI, 0.17–0.75; P = 0.007). Discussion This systematic review evaluated the effects of collagen membranes, e‐PTFE membranes, APCs and bone grafting materials, providing detailed information about the risks and benefits of using each regenerative technique/material or its combination in endodontic surgery. Conclusions Regenerative techniques improve periapical lesion healing after endodontic surgery. The combined use of collagen membranes and bovine‐derived hydroxyapatite may be beneficial as an adjunct to endodontic surgery. In contrast, the positive efficacy of e‐PTFE membranes or APCs alone remains doubtful.