As an interdisciplinary topic in psychology and public health, the relationship between personality traits and life outcomes has been extensively studied at the individual level. However, systematic investigations into their macro-level associations at the regional scale remain scarce. The rise of geographical psychology has revealed spatial distribution patterns of psychological phenomena—such as personality traits and cultural values—at the regional level, highlighting the unique value of state-level research as an intermediary perspective between individual- and national-level analyses. Accordingly, this study utilized data from all 50 U.S. states and incorporated multiple control variables to conduct correlation analyses at the state level between the Big Five personality traits and key life outcomes (life expectancy and various mortality rates) in an attempt to test the cross-level mechanism of “geographical environment → collective personality → health outcomes.” The results demonstrated that extraversion was significantly positively correlated with the mortality rates of diabetes (r = 0.176, p < 0.05) and motor vehicle accidents (r = 0.171, p < 0.05), and significantly negatively correlated with the drug-induced mortality rate (r = −0.284, p < 0.05). Agreeableness was positively correlated with the mortality rates of diseases such as diabetes and Alzheimer’s disease, and was significantly negatively correlated with the suicide mortality rate (r = −0.332, p < 0.05). Conscientiousness was associated with the death risks of multiple diseases. Neuroticism was negatively correlated with life expectancy (r = −0.353, p < 0.05) and positively correlated with the mortality rates of some diseases. Openness was negatively correlated with the mortality rates caused by factors like motor vehicle accidents (r = −0.256, p < 0.05). This study enhances our understanding of the interplay between regional psychological characteristics and the socioeconomic environment in shaping population health outcomes, while offering evidence-based insights for the development of place-specific health policies.