Background/Objectives: The clinical outcome of root canal treatments using calcium silicate-based sealer (CSBS) remains unclear. This study aimed to evaluate the 1-year effect of CSBS in combination with a single-cone obturation technique on periapical lesion (PL) healing evaluated on cone beam computed tomography scans (CBCT) after single-visit root canal retreatment. Methods: This randomized clinical study involved 50 patients with chronic apical periodontitis and previous root canal treatment (ClinicalTrials.gov ID: NCT04072926). The inclusion criteria were previous endodontic treatment, asymptomatic inadequate endodontic treatment, PLs measuring > 5 mm, and percussion and palpation sensitivity. The exclusion criteria were immunocompromised status, pregnancy, periodontally compromised teeth, vertical root fracture, and antibiotic usage in the last month. Single-visit root canal retreatment was performed by the same endodontist. The patients were randomly divided into two groups based on the root canal sealer used: CSBS (BioRoot RCS) and epoxy resin-based sealer (ERBS) (AH Plus). Periapical healing, as the primary outcome measure, was determined according to the reduction in PL volume on CBCT from the preoperative period to the 1-year postoperative period. Results: Pre- and postoperative PL volumes (p > 0.05) were not significantly different between the CSBS and ERBS groups. The success rate (loose criteria) was 82.9% in the ERBS group and 94.7% in CSBS group. Conclusions: Root canal retreatment outcomes of CSBS, including periapical healing, are comparable to those of ERBS at 1 year after the retreatment.