Aim: To evaluate and compare the success rates of single-visit and multiple-visit endodontic treatments in cases of apical periodontitis (AP) with periapical pathology. Materials and methods: In this randomized clinical trial, 51 patients who met the inclusion criteria were selected. Patients were randomly divided into three groups: single-visit group (group I), multi-visit group with calcium hydroxide as an intracanal medicament (group II), and multi-visit group with double antibiotic paste (DAP) as an intracanal medicament (group III). Comparison was done radiographically using the periapical index (PAI). The primary outcome measure was the change in periapical radiolucency after 9 months, assessed by PAI scores. Additionally, postoperative pain was evaluated after single- and multiple-visit root canal treatment using either of the medicaments after 24 hours, 48 hours, 72 hours, and 1 week. Data were analyzed using the Welch test and compared using the post hoc Tukey test (p < 0.05). The secondary outcome measures were assessed with the Chi-squared test. Results: No statistically significant difference in periapical healing was found between the three groups. Also, no statistically significant difference in postoperative pain was found between the three groups. Conclusion: Within the limitations, the results show that at the 9-month follow-up period, there was no difference in periapical healing and postoperative pain between single- and multi-visit treatments, either with DAP or calcium hydroxide as an intracanal medicament, for teeth with AP, considering that no treatment protocol is better than the other. Clinical significance: The success of endodontic therapy depends on the clinical judgment of the dentist to either perform single-visit or multi-visit endodontics. CTRI registration: CTRI/2022/07/043773.