Background: This is a systematic review to assess and provide a pooled effect estimate, if possible, for the effects of triple antibiotic paste as an intra-canal medication for root canal treatment of mature permanent non-vital teeth with apical periodontitis. This review will assess post-operative pain, flare-up incidence, and clinical and radiographic healing. Methods: Nine electronic databases (Pubmed, CENTRAL, VHL, Scopus, EBSCOhost, Web of Science, Trip, OpenGrey, Proquest) were searched along with two major clinical trial registries. Conference proceedings, reference lists and citations of the included studies were also searched. A total of 537 records were identified and 392 were obtained after duplicate removal. Six records were identified after screening and three studies were included after full text eligibility assessment. Results:  Three comparators were reported in the included studies: calcium hydroxide paste, 2% chlorhexidine gel and ledermix paste.  There was no statistically significant difference between triple antibiotic paste and calcium hydroxide regarding postoperative pain, and clinical and radiographic healing of periapical lesions. There was no difference between triple antibiotic paste and chlorhexidine regarding flare-up incidence. However, triple antibiotic paste reduced the level of post-operative pain more than ledermix, which was statistically significant. Conclusions:  The evidence is still insufficient surrounding the use of triple antibiotic paste; therefore more clinical investigations with high levels of evidence and rigorous methodologies are needed.