The study identified the adherence towards COVID-19 preventive measures and acceptance of the COVID-19 vaccine that is likely to be influenced by the population’s health literacy. Evidence suggested that knowledge, attitude, and practices (KAP) related to the COVID-19 pandemic play a crucial role in understanding the health-seeking behavior of the population. The study aimed to determine and examine the KAP related to the COVID-19 pandemic among the population in urban and rural settings of Tamil Nadu. A cross-sectional study was conducted from March 2021 to May 2021 among individuals enrolled from eight primary health centers (PHCs) in the state of Tamil Nadu, India.