Background and Objectives: Endodontic microsurgery (EMS) aims to eradicate the sources of infection once the apical root resection removes most of the infected anatomical structures and repairs potential procedural errors in the apical region. An endodontic-periodontal lesion yields a pathological communication between the pulp and the periodontium. The purpose of this systematic review and meta-analysis is to evaluate the impact of periodontal attachment loss on the outcome of teeth submitted to EMS. Materials and Methods: PRISMA guidelines were followed. An electronic search was performed in EBSCOhost, Embase and PubMed databases with the following search key: (“endodontic microsurgery” AND “outcome”). No filters were used concerning the year of publication or language. Only randomized clinical trials, prospective and retrospective clinical studies in humans, with a minimum one-year follow-up, defined clinical and radiographic outcome criteria and estimable success rate for endodontic-periodontal lesion were included. Statistical analysis was performed using OpenMeta[Analyst] software. Results: Of a total of 113 articles, 34 were selected for full-text reading after duplicates deletion and title and abstract analysis. Thirteen and six studies were included in the systematic review and meta-analysis, respectively. A total of 2775 pooled teeth were submitted to EMS, of which 492 teeth and 4 roots had periodontal involvement. According to the qualitative analysis, success rates of the endodontic-periodontal group ranged from 67.6% to 88.2%. Meta-analysis revealed that the absence of periodontal attachment loss was predictive of a higher likelihood of success with an odds ratio of 3.14. Conclusions: Periodontal attachment loss presents a risk factor for EMS outcome. Although endodontic-periodontal lesions were associated with lower success rates considering a 1 to 10 years follow-up period, long-term successful prognosis following EMS has been reported, therefore presenting a fully valid and viable therapeutic option for the management of this type of lesions.