Non-pharmaceutical interventions (NPIs) involving social-isolation strategies such as self-quarantine (SQ) and social-distancing (SD) are useful in controlling the spread of infections that are transmitted through human-to–human contacts, e.g., respiratory diseases such as COVID-19. In the absence of a safe and effective cure or vaccine during the first ten months of the COVID-19 pandemic, countries around the world implemented these social-isolation strategies and other NPIs to reduce COVID-19 transmission. But, individual and public perception play a crucial role in the success of any social-isolation measure. Thus, in spite of governments’ initiatives to use NPIs to combat COVID-19 in many countries around the world, individual choices rendered social-isolation unsuccessful in some of these countries. This resulted in huge outbreaks that imposed a substantial morbidity, mortality, hospitalization, economic, etc., toll on human lives. In particular, human choices pose serious challenges to public health strategic decision-making in controlling the COVID-19 pandemic. To unravel the impact of this behavioral response to social-isolation on the burden of the COVID-19 pandemic, we develop a model framework that integrates COVID-19 transmission dynamics with a multi-strategy evolutionary game approach of individual decision-making. We use this integrated framework to characterize the evolution of human choices in social-isolation as the disease progresses and public health control measures such as mandatory lockdowns are implemented. Analysis of the model illustrates that SD plays a major role in reducing the burden of the disease compared to SQ. Parameter estimation using COVID-19 incidence data, as well as different lockdown data sets from India, and scenario analysis involving a combination of Voluntary-Mandatory implementation of SQ and SD shows that the effectiveness of this approach depends on the type of isolation, and the time and period of implementation of the selected isolation measure during the outbreak. © 2021 Elsevier Ltd