The aim of the present study was to conduct a systematic review and critical analysis of published data on irrigant extrusion to identify factors causing, affecting or predisposing to irrigant extrusion during root canal irrigation of human mature permanent teeth. An electronic search was conducted in Cochrane Library, LILACS, PubMed, SciELO, Scopus and Web of Knowledge using a combination of the terms ‘irrigant’, ‘rinse’, ‘extrusion’, ‘injection’, ‘complication’, ‘accident’, ‘iatrogenic’, ‘root canal’, ‘tooth’ and ‘endodontic’. Additional studies were identified by hand-searching of six endodontic journals and the relevant chapters of four endodontic textbooks, resulting in a total of 460 titles. No language restriction was imposed. After applying screening and strict eligibility criteria by two independent reviewers, 40 case reports and 10 ex vivo studies were included in the review. A lack of clinical studies focusing on irrigant extrusion during root canal irrigation was evident. The reviewed case reports focused mainly on the clinical manifestations and management of the accidents and did not provide adequate details on the possible factors that may influence irrigant extrusion. The data from the included ex vivo studies were inconclusive due to major methodological limitations, such as not simulating the presence of periapical tissues and not assessing the validity of irrigant detection methods. The extensive variability in the protocols employed hindered quantitative synthesis. The choice of factors investigated in ex vivo studies seems not to have been driven by the available clinical evidence. These issues need to be addressed in future studies.