Background Fibrous dysplasia (FD) and cemento‐ossifying fibroma (COF) are the most common gnathic fibro‐osseous lesions. These diseases exhibit remarkable overlap of several clinicopathological aspects, and differential diagnosis depends on the combination of histopathological, radiographic, and clinical aspects. Their molecular landscape remains poorly characterized, and herein, we assessed their proteomic and phosphoproteomic profiles. Methods The quantitative differences in protein profile of FD and COF were assessed by proteomic and phosphoproteomic analyses of formalin‐fixed paraffin‐embedded tissue samples. Pathway enrichment analyses with differentially regulated proteins were performed. Results FD and COF exhibited differential regulation of pathways related to extracellular matrix organization, cell adhesion, and platelet and erythrocytes activities. Additionally, these lesions demonstrated distinct abundance of proteins involved in osteoblastic differentiation and tumorigenesis and differential abundance of phosphorylation of Ser61 of Yes‐associated protein 1 (YAP1). Conclusions In summary, despite the morphological similarity between these diseases, our results demonstrated that COF and DF present numerous quantitative differences in their proteomic profiles. These findings suggest that these fibro‐osseous lesions trigger distinct molecular mechanisms during their pathogenesis. Moreover, some proteins identified in our analysis could serve as potential biomarkers for differential diagnosis of these diseases after further validation.