Background/Objectives: This study aims to investigate the influence of root canal morphology and various treatment variables on the outcomes of root canal treatments (RCT) in mandibular second molars, assessed through cone-beam computed tomography (CBCT) imaging. Methods: A total of 150 CBCT images were examined, comprising 100 cases of persistent endodontic infections and 50 from previously treated root canals with normal apices in mandibular second molars. CBCT was utilized to evaluate root canal configuration, the radiographic quality of coronal restorations and treated canal systems, and the presence of periapical lesions. Statistical analyses were performed to explore correlations between these factors. Results: The presence of a C-shaped root canal configuration did not demonstrate a significant correlation with periapical lesions (p=0.05). Factors influencing endodontic treatment outcomes included the presence of missing canals (p=0.018), underfilling or overfilling (p=0.045), and inadequate coronal restoration (p=0.006). The presence of a missing canal was identified as the variable most significantly associated with periapical lesions (OR=3.103). Leaky canals were more commonly observed in C-shaped root canals (p<0.001). Conclusions: Regardless of the root canal morphology of mandibular second molars, successful RCT depends on thorough disinfection to eliminate any untreated canals, precise three-dimensional filling of the canals at the correct working length, and a securely sealed coronal restoration to prevent leakage.