Context: Is it possible that the irrigating solutions can have the potential to cause post-operative pain? Unfortunately, the current literature does not provide clear guidance. Aim: The purpose of this systematic review and meta-analysis was to comprehensively review two different irrigation solutions (sodium hypochlorite and chlorhexidine) regarding the post-operative pain after endodontic treatment. Settings and Design: This study was prepared according to the Cochrane criteria for creating a systematic review and meta-analysis and confirms the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Material and Methods: This search was conducted in the PubMed/MEDLINE, SCOPUS and Cochrane Library databases until February 2018 to answer the In [(Population) what is the effect of (Intervention) on (Outcome), compared with (Comparison) Intervention] (PICO) question: could sodium hypochlorite cause more post-operative pain than chlorhexidine in teeth subjected to endodontic treatment? The primary outcome was overall post-operative pain after 24 h. Results: After applying the inclusion and exclusion criteria, three randomized clinical trials fulfilled the eligibility criteria, and two were subjected to the meta-analysis. There was no difference in post-operative pain between the tested irrigating solutions. Conclusions: There are few studies published in the current literature; therefore, additional randomized clinical studies are required to on this topic to help clinicians make the best decision concerning treatment.