COVID-19 has led to global dramatic shifts in daily life. Following the biopsychosocial model of health, the goal of the current study was to predict people's psychological well-being (PWB) during the initial lockdown phase of the pandemic and to investigate which coping strategies were most common among people with low and high PWB. Participants were 938 volunteers in the United States who responded to an online survey during the lockdown in April 2020. The main findings were that all three groups of variables, biological, psychological, and socio-economic, significantly contributed to PWB explaining 53% variance. Social loneliness and sense of agency were the strongest predictors. PWB was significantly predicted by physical health (not gender nor age); by spirituality, emotional loneliness, social loneliness, and sense of agency; by job security (not income, nor neighborhood safety, nor hours spent on social media). Comparing the coping strategies of participants, results show more intentional coping in the high-PWB group and more passive coping in the low-PWB group. During this unprecedented pandemic, the findings highlight that ability to sustainably cope with the global shifts in daily life depends on actively and intentionally attending to PWB by being one's own agent for physical health, spiritual health, and social connection.