The aim of this study was to compare the effect of two calcium silicate-based and an epoxy resin-based root canal sealers on postoperative pain and analgesic intake following single-visit root canal treatment. Ninety patients with at least one first or second molar tooth diagnosed as symptomatic irreversible pulpitis and symptomatic apical periodontitis were selected and allocated into three groups (n=30) according to the sealer used. Root canals were prepared using Protaper Gold instruments (Dentsply Sirona) in a crown down technique and irrigated with 2.5% NaOCl (Calyx, India) and saline solution. Root canal filling was then accomplished with a single cone obturation technique and treated in a single visit by the same endodontist. Patients were told to use a Visual Analog Scale (VAS) to rate their postoperative pain severity as none, minimal, moderate, or severe after 6 h, 24 h, 48 h, 5 days and 7 days following obturation using the appropriate sealers. The need for analgesic intake was also recorded. The data were statistically analyzed. Results showed a significant difference among the studied groups. Bio-C Sealer Ion+ reported the least pain score followed by Nishika Canal Sealer BG and AH plus sealer at all the time intervals recorded. The intergroup analysis, revealed was a significant difference in postoperative pain at 6 h (p=0.000) and 24 h (p = 0.028), but not at 48 h, 5 day or 7 days (P > 0.05). VAS ratings for all the three groups decreased over time. Also, there were significant differences between the means of analgesic intake among 3 groups (p=0.022). Analgesic intake in group BIO-C Sealer Ion+ is significantly lesser than AH Plus and Nishika Canal Sealer BG group. Calcium silicate-based sealer (Nishika Canal Sealer BG and Bio-C Sealer Ion+) resulted in significantly lower levels of pain as compared to epoxy resin-based sealer (AH Plus) at 6h and 24-h interval, there was no significant difference in postoperative pain occurrence at 48-h, 5 day and 7-day period. The analgesic intake in Bio-C Sealer Ion+ group is significantly lesser than Nishika Canal Sealer BG and AH Plus group.