Purpose The aim of this study was to investigate the effectiveness of cone-beam CT (CBCT) findings and gray scale values (GSV) in the differential diagnosis of apical cysts and granulomas. Methods Two independent researchers retrospectively analyzed the CBCT images of 21 teeth and histopathologically diagnosed them as having radicular cysts or apical granulomas. In the CBCT images, apical lesions were evaluated and categorized according to 7 criteria. These criteria were determined as relationship of lesions with dental roots, periphery of the lesion, shape, darker focus in the center, root resorption, displacement in related teeth, and cortical bone perforation. In addition, the minimum and maximum gray scale values of the lesions were measured and compared. Results There was a statistically significant relationship between histopathological (HP) diagnosis and well-defined cortical border and lesion shape (p = 0.003,p = 0.014, respectively). According to the HP diagnosis, no statistically significant difference was found among other variables (p > 0.05) Conclusion The presence of a well-defined cortical border or partial cortical border is a distinctive criterion for cysts. Additionally, the shape of the lesion was found to be a significant criterion for the separation of the two lesions. The shape of cystic lesions was circular and apical granulomas had a more curved shape. There was no relationship between the histopathological diagnosis of lesions and CBCT gray scale values.