Background The aim of this systematic review and meta-analysis was to furnish evidence-based recommendations for the utilization of bioceramic-based and resin-based sealers in clinical endodontics, with a focus on reducing postoperative discomfort. Methods The investigation’s methodology was registered on the International Prospective Database of Systematic Reviews (PROSPERO: CRD42022355506) and executed using the 2020 PRISMA protocol. Articles were selected utilizing the PICO technique and applying specific inclusion and exclusion criteria. Articles published between January 2000 and August 2022, PubMed, MEDLINE, and DOAJ were utilized as primary data sources. After the identification of studies, two autonomous reviewers evaluated the titles and abstracts, and data from qualifying studies were extracted. Results Nine published studies were included in this analysis. The findings indicate that there were no significant differences in the Visual Analog Scale (VAS) scores between resin-based and bioceramic root canal sealers at intervals of 6 hours, 12 hours, 24 hours, and 48 hours after treatment. Conclusion The findings of this systematic review and meta-analysis suggest that after the utilization of bioceramic sealers during root canal therapy, the pain and discomfort levels were not significantly different from those experienced pain after the use of resin-based sealers.