Protein kinase B (Akt) plays a very significant role in various cancers including oral cancer. However, it has three isoforms (Akt1, Akt2, and Akt3) and they perform distinct functions and even play contrasting roles in different cancers. Therefore, it becomes essential to evaluate the isoform-specific role of Akt in oral cancer. In the present study, an attempt has been made to elucidate theisoform-specific role of Akt in oral cancer. The immunohistochemical analysis of oral cancer tissues showed an overexpression ofAkt1 and 2 isoforms but not Akt3. Moreover, the dataset of “The Cancer Genome Atlas” for head and neck cancer has suggested thegenetic alterations of Akt1 and 2 tend to be associated with the utmost poor clinical outcome in oral cancer. Further, treatment of oralcancer cells with tobacco and its components such as benzo(a)pyrene and nicotine caused increased mRNA levels of Akt1 and 2isoforms and also enhanced the aggressiveness of oral cancer cells in terms of proliferation, and clonogenic and migration potential.Finally, silencing of Akt1 and 2 isoforms caused decreased cell survival and induced cell cycle arrest at the G2/M phase. Akt1/2 silencing also reduced tobacco-induced aggressiveness by decreasing the clonogenic and migration potential of oral cancer cells.Moreover, silencing of Akt1 and 2 isoforms was found to decrease the expression of proteins regulating cancer cell survival andproliferation such as cyclooxygenase-2, B-cell lymphoma 2 (Bcl-2), cyclin D1, and survivin. Thus, the important role of Akt1 and 2isoforms have been elucidated in oral cancer with in-depth mechanistic analysis.