Objectives <p>This randomized clinical trial aimed to evaluate the effect of calcium hydroxide-based, calcium silicate-based and epoxy resin-based root canal sealers on postoperative pain (PP) after a single session of non-surgical endodontic retreatment of the teeth with chronic apical periodontitis.</p> Materials and methods <p>Ninety-six participants who had teeth with previously root canal treatment, asymptomatic, a single root and single canal, chronic apical periodontitis, were included in the study and then were randomly allocated to one of three experimental groups. (<i>n</i> = 32 per group).An endodontic specialist performed same retreatment protocols in a single visit. Participants were asked to rate the intensity of PP on a visual analogue scale at 6, 12, 24, and 48&#xa0;h, and 3, 4,5, 6, and 7 days, and to mark whether they had taken analgesic (400&#xa0;mg Ibuprofen) during the same periods after retreatment. All statistical analyses were performed using a software program (IBM SPSS Statistics, Version 22), and the significance level was set at <i>P</i> &lt; 0.05.</p> Results <p>There was no significant difference between the groups in PP and analgesic intake at any of the time intervals evaluated(<i>P</i> &gt; 0.05).A strong positive correlation was observed at 48&#xa0;h and 96&#xa0;h when the correlation between PP and analgesic intake was evaluated regardless of the type of root canal sealer. PP level was associated with age, gender, Periapical Index (PAI) score, and jaw type.(<i>P</i> &lt; 0 0.05).</p> Conclusions <p>Epoxy resin, Calcium silicate, and calcium hydroxide–based root canal sealers resulted in statistically similar postoperative pain levels.</p> Clinical significance <p>Each of the epoxy resin, calcium silicate, and calcium hydroxide-based root canal filling materials could be used safely in patients when considering PP.</p> Trial registration <p>ClinicalTrial.gov, NCT06803277, record date: 2025-01-17, retrospectively registered.</p>