OBJECTIVE Post-operative pain may occur after non-surgical root canal treatment (NSRCT). The root filling technique and choice of sealer may be contributing factors. This randomized controlled clinical trial compared post-operative pain and analgesics intake after NSRCT using a sealer-based obturation technique (SBO) with single-cone gutta-percha and calcium silicate sealer (CSS) versus a warm-vertical compaction (WVC) technique with gutta-percha and a resin-based sealer (RBS). METHODS This study was designed as a parallel-two arm, double-blind, randomized superiority clinical trial registered at www. RESULTS gov (NCT04753138). Patients referred for NSRCT fulfilling the inclusion criteria participated in this study. Pre-operative periapical radiographs and CBCT scans were taken and numerical rating scale (NRS) pain scores were recorded. Upon completion of canal instrumentation, participants were randomly allocated to either Group SBO: SBO with CSS or Group WVC: Warm-vertical compaction with RBS. Post-operative pain and analgesics intake were recorded at 1, 3 and 7 days after endodontic treatment completion. Non-parametric Mann-Whitney U and Friedman tests and a generalized estimating equation were used to assess differences in pain scores between the groups, within each treatment group at different time points and for correlations, respectively. RESULTS The study included 195 participants (212 teeth). One participant declined to submit the NRS form. Therefore, 194 participants (211 teeth) were included in the final analysis (99.5% response rate). No statistically significant differences in post-operative pain or analgesic intake existed between the two groups at any time point (p > .05). Age, pre-operative pain, apical diagnosis and post-operative analgesic intake were significantly related to post-operative pain (p < .05). CONCLUSIONS Sealer-based obturation technique with CSS was associated with similar post-operative pain levels and analgesics intake as WVC with RBS. Regarding post-operative pain, SBO with CSSs may be a suitable clinical alternative.