Background: The effectiveness of final root canal irrigants is crucial for successful conventional and regenerative endodontic treatments. This study aimed to systematically review the impact of final irrigants on dentin, disinfection, and regenerative potential in endodontic therapies. Methods: MEDLINE, Cochrane Library, and Web of Science databases were electronically searched for articles on final irrigants in conventional and regenerative endodontics, evaluating effects on dentin, smear layer, fracture resistance, stem cells, growth factors, and antimicrobial properties. The risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool. Results: Overall, 25 eligible studies were included in this review after screening 2842 articles. Commonly assessed irrigants included ethylenediaminetetraacetic acid (EDTA) (21 studies), sodium hypochlorite (NaOCl; 12 studies), and citric acid (6 studies). EDTA could enhance growth factors but could weaken dentin. NaOCl affected dentin despite its antimicrobial benefits. Nanoparticles, chitosan, peracetic acid (PAA), and citric acid showed potential benefits. A meta-analysis was not performed due to methodological heterogeneity. Conclusion: In general, optimized irrigation strategies balancing disinfection, biocompatibility, and regenerative potential are necessary. More research is required to develop improved irrigation protocols. Registration: PROSPERO CRD42023420406.