Introduction: The middle mesial canal (MMC) of mandibular molars is of particular interest in endodontics due to its complexity. This study investigated the association between MMC presence in first and second mandibular molars and the radiolucency in the furcation area using cone-beam computed tomography (CBCT) scans. Materials and Methods: CBCT scans of 400 patients referred to the largest radiology center in Kerman City from January 1, 2022, to January 1, 2023, were examined. All CBCT scans were assessed for radiolucency in the furcation area and the presence of MMC. Variables, including age, gender, tooth number, and MMC presence were recorded. Chi-squared tests and logistic regression analyses were employed to compare MMC frequency and its impact on furcation radiolucency. Results: Of 201 examined teeth, 37 (18.4%) had MMC, and 23 (11.4%) exhibited furcation radiolucency. However, teeth with a mesial canal showed a higher prevalence of furcation lesions compared to those without (38% vs. 5.2%) (P<0.001). A significant association was observed between a mesial canal and furcation radiolucency, with odds of furcation radiolucency at 12.7 after controlling for age and gender (P<0.001). Conclusion: A strong association exists between MMC presence in first and second mandibular molars and furcation radiolucency, unaffected by age and gender.