Odontogenic keratocyst is classified under developmental cyst which develops from cell rest of dental lamina. It has no specific predilection for age and can occur from infancy to old age, however with a slight predilection for males. The mandibular posterior region is most commonly affected. The cyst has high chances of recurrence. One of the most important radiographic features is that the cyst tends to expand antero-posteriorly within the medullary cavity of the bone without causing bony expansion. A case with odontogenic keratocyst of the left posterior mandible is discussed with clinical and radiographic findings. Clinical examination revealed buccal lymphadenitis with obliteration and tenderness over the left mandibular buccal vestibule. Radiographic examination such as intraoral periapical (IOPA) radiograph and orthopantomogram revealed a multilocular lesion with mixed densities involving the apices of the left mandibular posterior teeth. The corresponding third molar was impacted and the inferior alveolar nerve canal was displaced inferiorly. There was no bony expansion evident on the occlusal radiograph. The features were suggestive of odontogenic keratocyst. How to cite this article: Malairaj Y, Reddy J. Differential Diagnosis of a Multilocular Radiolucency of the Mandible: A Case Report. J Sci Dent 2020;10(2):46–48.