According to the parasite-stress theory, collectivism serves as a trait of ingroup assortative sociality, providing defense against infectious diseases. This study investigated the association between cultural collectivism and COVID-19 severity at the state (Study 1: N = 51), county (Study 2: N = 3,133), and daily (Study 3: N = 52,806) levels from the beginning of 2020 to the end of 2022. State-level collectivism was assessed using two distinct measures: the U.S. collectivism index, focusing on social interconnectedness and interdependence, and the subjective-culture individualism-collectivism index (reversed), capturing attitudes and beliefs related to religion, abortion, and same-sex marriage. By employing random-intercept multilevel models, the results demonstrated significant and negative effects of state-level collectivism, as measured by the U.S collectivism index, on COVID-19 cases per million, COVID-19 deaths per million, and composite COVID-19 severity index, after controlling for confounding factors, such as socioeconomic development, ecological threats, disease protective behaviors, cultural norms, and political influences. A mini meta-analysis (Study 4: N = 9) confirmed the significance of these effects across studies. These findings supported the proactive role of collectivism in defending against the novel coronavirus in the United States, aligning with the parasite-stress theory of sociality. However, the subjective-culture individualism-collectivism index (reversed) did not exhibit a significant relationship with COVID-19 severity when confounding factors were considered. The high correlation between the subjective-culture individualism-collectivism index (reversed) and the controlled variables suggested shared variance that could diminish its impact on COVID-19 outcomes. Accordingly, the present findings underscore the significance of accounting for confounding factors when examining the association between collectivism and COVID-19 severity at population level. By considering relevant confounding factors, researchers could gain a comprehensive understanding of the complex interplay between cultural collectivism and its influence on COVID-19 severity. Overall, this research contributes to our understanding of how cultural collectivism shapes the COVID-19 pandemic in the United States, emphasizing the importance of adjusting for confounding effects in population level studies.