Aim:The aim of this study is to compare the incidence of postoperative pain using the ProTaper Next (PTN), WaveOne Gold (WOG), and Self-Adjusting File (SAF) systems.Materials and Methods:Two hundred and fourteen patients with irreversible pulpitis were selected for single-visit endodontics. The teeth were blindly assigned to three groups based on the instrumentation system used: Group A (PTN), Group B (WOG), and Group C (SAF). Participants were asked to note the incidence of the pre- and postoperative pain on a visual analog scale at different time intervals. Paired t-test and one-way ANOVA were used along with post hoc Tukey's test.Results:The greatest mean pain in Group A (PTN) and Group B (WOG) was found to be maximum in the first 24 h with a significant reduction in pain at the subsequent observation time points of 48 h, 72 h, and 7 days. Group C (SAF) showed minimum pain followed by Group B followed by Group A which showed comparatively higher pain scores even at the end of 7 days.Conclusions:In single-visit endodontics, SAF system may prove to be a better system compared with PTN and WOG as it produces minimal postoperative pain, thus improving the overall acceptance of endodontic treatment.