The aim of this paper is to systematically analyse the effect of calcium silicate-based sealers in comparison to resin-based sealers on clinical and radiographic outcomes of non-surgical endodontic treatment in permanent teeth. Methods: The study was conducted according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. The literature search was performed using PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, DOAJ and OpenGrey with no language restrictions. Two reviewers critically assessed the studies for eligibility. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was carried out to assess the evidence. Meta-analysis of the pooled data with subgroups was carried out using the RevMan software (p < 0.05). Results: Results from the included studies showed that there were no significant differences between the groups in the 24 h post-obturation pain levels (mean difference (MD), −0.19, 95% CI = −0.43–0.06, p = 0.14, I2 = 0%), but at 48 h (MD, −0.35, 95% CI = −0.64–0.05, p = 0.02, I2 = 0%), a significant difference was observed in favour of calcium silicate sealers. Furthermore, there were no significant differences between the two sealers due to risk of onset or intensity of postoperative pain, need for analgesic and extrusion of the sealer. The heterogeneity assessed using Q test between the included studies was 97% (I2). Conclusions: Within the limitations of this review, the paper shows that calcium silicate-based sealers exhibited optimal performance with similar results to resin-based sealers in terms of average level of post-obturation pain, risk of onset and pain intensity at 24 and 48 h. The observations from the included studies are informative in the clinical evaluation of calcium silicate-based sealers and provide evidence for the conduction of well-designed, controlled randomised clinical trials for a period of at least four years in the future.