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Aim This study was intended to compare syringe irrigation versus two irrigation agitation protocols [manual dynamic agitation (MDA) and passive ultrasonic irrigation] regarding postoperative pain (PP) after chemo-mechanical preparation of mandibular first molars with irreversible pulpitis and symptomatic apical periodontitis using numerical rating scale. Participants and methods Ninety patients with mandibular first molars diagnosed as symptomatic irreversible pulpitis with apical periodontitis were included in this study. Teeth were classified into three groups (n = 30) according to the final irrigation agitation protocol used. Root canals were irrigated using 5.25% sodium hypochlorite using the following protocols; group A: NaviTip (31-G 27 mm) with double side-port irrigator tip (side vented needle). Group B: MDA with well fitted master cone. Group C: ultrasonic activation using Endo ultra. PP was evaluated after 6, 12, 24, 48, and 72 h and 1 week. Level of confidence at 95% was used for statistical significance. Results Severity of PP was significantly more intense at 6-12 and 24-h time intervals in group B patients than groups A and C (P < 0.05). There was no significant difference among all groups at the other time intervals (P > 0.05). Conclusion After chemo-mechanical preparation in mandibular first molars with symptomatic irreversible pulpitis and apical periodontitis, MDA caused greater PP in comparison with the other irrigation agitation protocols in the first 24 h. Severity of PP in all groups decreased over time. [ABSTRACT FROM AUTHOR]