Background Central giant cell granuloma (CGCG) presents as a locally invasive, intraosseous lesion characterized by the accumulation of multinucleated giant cells amidst a matrix of hemorrhage and reactive fibrous tissue that infiltrates bone trabeculae. This idiopathic non-neoplastic proliferative lesion primarily affects the mandible, typically presenting as either unilocular or multilocular radiolucencies on X-rays. Although trauma or intraosseous hemorrhages are potential triggers, the precise histogenesis and etiology remain unclear. CGCG predominantly occurs in children and young adults, with a slight female predilection. Methods and materials A retrospective analysis of 21 cases of CGCG diagnosed at the Oral Pathology/Pathology department of Temple University Hospital between 2015 and 2022 was conducted. Each case was evaluated based on various parameters, including age, gender, presenting symptoms, radiographic findings, clinical differential diagnosis, and histological confirmation. The primary radiographic technique employed for diagnosis was X-ray imaging of the mandible and maxilla. The histological examination involved cutting paraffin-embedded tissue into 5-micrometer-thick sections, which were then stained using routine hematoxylin and eosin (H&E) stain. Notably, no specialized histochemical or immunohistochemical stains were utilized in the evaluation process. Results In our study, we reviewed 21 cases; 9 were male, 11 were female, and one had no available gender data.The age range was 15-76 years, with a mean of 50 years. The mandible was the most commonly affected location (17 cases; 81%)while the maxilla was less commonly involved (4 cases; 19%). Many CGCG lesions were asymptomatic (13 cases; 62%); eight cases (38%) were symptomatic, with painand fullness of the affected dental region being the main manifestations. In a few cases, conditions such as brown tumor (severe hyperparathyroidism) and odontogenic neoplasms, such as ameloblastoma, were suspected clinically and radiographically. The diagnosis of CGCG with associated acute and chronic inflammation was confirmed in all the cases. Histological evaluation of routinely stained slides was the main diagnostic tool utilized. No special stains or molecular studies were required to establish the final diagnosis. Conclusions Our investigation has determined that CGCG exhibits a non-neoplastic nature, displaying a spectrum of behaviors ranging from non-aggressive to aggressive tendencies. While CGCG is predominantly observed in the mandible, rare instances of involvement in the maxilla have also been documented. Importantly, no confirmed association with neoplastic lesions was identified during our analysis. The clinical course of CGCG tends to be indolent, with some cases presenting in association with impacted teeth. It's noteworthy that CGCG can present features mimicking neoplastic conditions, such as ameloblastoma, or localized lesions linked to systemic disorderssuch as hyperparathyroidism (brown tumor).