This work aimed to investigate the use of Regenerative Endodontic Procedures (REP) on the treatment of pulp necrosis in mature teeth through systematic review and meta-analysis of evidence on clinical and radiographic parameters before and after REP. A search was performed in different databases on 9 September 2020, including seven clinical studies and randomized controlled trials (RCT). The methodological quality was assessed using Revised Cochrane risk-of-bias (RoB 2) and Before-and-After tools. Meta-analyses were performed to evaluate the success incidences regarding the reduction of periapical lesion and recovery of sensitivity. The certainty of the evidence was assessed using GRADE. Meta-analysis showed a high overall success of 0.95 (0.92, 0.98) I² = 6%, with high periapical lesion reduction at 12 months (0.93 (0.86, 0.96) I² = 37%) and by the end of follow-up (0.91 (0.83, 0.96) I² = 13%). Lower incidences of positive sensitivity response were identified for the electrical (0.58 (0.46, 0.70) I² = 51%) and cold tests (0.70 (0.54, 0.84) I² = 68%). The calculated levels of REP success were similar to those reported for immature teeth. With a very low certainty of evidence, the meta-analysis showed a high incidence of REP’s success for mature teeth with necrotic pulp evidenced by periapical lesion reduction and moderate positive responses to sensitivity tests.