Aim and objective: ErbB2 also referred to as CD340, HER2/neu belongs to the human epidermal growth factor receptor (EGFR) family. It is a cell surface receptor kinase involved in the regulation of important events like cell proliferation and differentiation. Phosphorylation of ErbB2 by their ligands causes activation of downstream signaling pathways like phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-Akt pathways. To evaluate the role of ErbB2 in odontogenic keratocysts (OKCs), dentigerous cyst (DC), and ameloblastoma by correlating the expression levels of ErbB2 with the biological behavior of the disease. Materials and methods: The present study comprises 10 histopathologically diagnosed FFPE samples, of OKC, DC, and ameloblastoma among odontogenic lesions. These cases were subjected to immunohistochemical staining with ErbB2 antibody. ASCO/CAP scoring criteria 2013 was employed for interpretation. Membranous reactivity was considered positive. Mann–Whitney U test was used for statistical analysis. Results: The ErbB2 expression levels in nine cases of OKC tissue showed significantly high expression, followed by eight cases of ameloblastoma, and five cases of a DC. All these odontogenic lesions showed positive for cell membrane staining. Conclusion: In the present study, HER2 is highly expressed in the majority of cases of OKC and ameloblastoma. However, further studies with a larger sample size have to be carried out along with other members of the ErbB2 family for definitive inference. Clinical significance: Increased expression of ErbB2 indicates neoplastic transformation.