Background <p>The aim of this study was to evaluate the effect of ultrasonic, sonic, and Er: YAG laser activations on postoperative pain during single-visit non-surgical endodontic retreatment of asymptomatic maxillary anterior teeth with periapical lesions following initial root canal treatment performed at least four years earlier.</p> Methods <p>Seventy-five asymptomatic maxillary anterior teeth with periapical lesions following initial root canal treatment performed at least four years earlier were included. Root canal filling materials were removed using Remover rotary (Coltene MicroMega, Besançon, France) and H-type hand files and canals were reshaped with step-back technique. Final irrigation was performed with one of the activation systems: group 1: Ultra X (Eighteeth), group 2: EDDY (VDW), group 3: Er: YAG laser (LightWalker, Fotona). EDTA followed by NaOCl were activated in three cycles of 20&#xa0;s in all groups. Canals were obturated with gutta-percha and BioRoot RCS and restored with composite. Pain levels were recorded using Visual analog scale (VAS) immediately after completion of treatment (0&#xa0;h), and at 6, 12, 24, 48, 72&#xa0;h, and on 7th day. Pearson Chi-square, Fisher’s Exact, and robust mixed repeated-measures analysis of variance tests were used for statistical analysis.</p> Result <p>No flare-ups occurred, and no analgesic medication was required. The activation systems had a comparable effect on postoperative pain at any time point (<i>p</i> &gt; 0.05). Postoperative pain did not exhibit any statistically significant time-dependent differences with any of the activation devices within each group.</p> Conclusion <p>Ultrasonic, sonic, and laser-assisted irrigation activation demonstrated comparable effects on postoperative pain in asymptomatic maxillary anterior teeth undergoing single-visit non-surgical endodontic retreatment.</p> Trial registration <p>This study was registered at ClinicalTrials.gov (NCT07150585) on 29/08/2025. Retrospectively registered.</p>