Recognizing an urgent need to understand the dynamics of the pandemic’s severity, this longitudinal study is conducted to explore the evolution of complex relationships between the COVID-19 pandemic, lockdown measures, and social distancing patterns in a diverse set of 86 countries. Collecting data from multiple sources, a structural equation modeling (SEM) technique is applied to understand the interdependencies between independent variables, mediators, and dependent variables. Results show that lockdown and confinement measures are very effective to reduce human mobility at retail and recreation facilities, transit stations, and workplaces and encourage people to stay home and thereby control COVID-19 transmission at critical times. The study also found that national contexts rooted in socioeconomic and institutional factors influence social distancing patterns and severity of the pandemic, particularly with regard to the vulnerability of people, treatment costs, level of globalization, employment distribution, and degree of independence in society. Additionally, this study portrayed a mutual relationship between the COVID-19 pandemic and human mobility. A higher number of COVID-19 confirmed cases and deaths reduces human mobility and the countries with reduced personal mobility have experienced a deepening of the severity of the pandemic. However, the effect of mobility on pandemic severity is stronger than the effect of pandemic situations on mobility. Overall, the study displays considerable temporal changes in the relationships between independent variables, mediators, and dependent variables considering pandemic situations and lockdown regimes, which provides a critical knowledge base for future handling of pandemics. It has also accommodated some policy guidelines for the authority to control the transmission of COVID-19.