Objectives: This study aimed to compare the postoperative pain and clinical performance after applying three different intracanal medicaments and root canal sealers. Materials and Methods: Sixty-five patients requiring root canal treatment due to symptomatic apical periodontitis were included in this study. After a glide path preparation by using PathFile, each canal was shaped with ProTaper Next file system. After the canal cleaning and shaping procedure, the canal was dried and each intracanal medicaments were adjusted (Calcipex II, TRC-paste, Metapaste). At the next visit, the patients were requested to answer the absence of the pain after the procedure. Once the patients showed no symptom, the canal was obturated with each corresponded root canal sealers (AH plus, Radic-sealer, ADseal). The patients were recalled after 1 week, 1, 3, and 6 months to check the postoperative pain or unexpected clinical signs. One-way ANOVA and Duncan's post hoc comparison, and Chi-square test were used for statistical analysis to evaluate any differences among tested materials. Results: The average number of visits for intracanal medication was 2.69, 2.65, and 2.61 for Calcipex II, TRC-paste, and Metapaste. There were no statistically differences in post-obturation pain among three groups obturated with different root canal sealers (P > 0.05). Conclusions: Under the limitations of this study, three tested intracanal medicaments and epoxy resin root canal sealers showed clinically acceptable similar results.