AbstractThe recent increase in high‐risk human papillomavirus (HR‐HPV)‐associated oral and oropharyngeal cancers has gained considerable importance due to their distinct clinical and molecular characteristics. However, the natural history of oral HPV from acquisition to persistence and malignant transformation is still unclear. The global prevalence of oral HPV infection in healthy individuals ranges from 0.67% to 35%, while 31%–38.5% in head and neck cancer (HNC). The persistence rate of oral HR‐HPV infection is 5.5% –12.8% globally. India has the highest HNC burden due to apparent differences in predisposing factors compared with the West. The prevalence of oral HPV in healthy individuals and its contribution to HNC is less evident in Indian studies. HR‐HPV‐associated HNC in this region accounts for 26%, with an active infection in 8%–15% of these tumors. There is a lack of concordance in the expression of p16 as a surrogate marker for HPV detection in HNC because of differences in behavioral risk factors. Due to a lack of evidence, treatment de‐escalation cannot be implemented despite the improved outcome of HPV‐associated oropharyngeal cancers. This review critically analyzes the existing literature on the dynamics of oral HPV infection and HPV‐associated HNC, identifying potential avenues for future research. A better understanding of the oncogenic role of HR‐HPV in HNC will help to formulate novel therapeutic approaches and is expected to have a significant public health impact as preventive strategies can be implemented.