To investigate whether there is an association between gene polymorphisms, genetic and environmental interactions, and psychological stress reactivity in Chinese subjects living in the Guangxi minority region. This cross-sectional study enrolled subjects older than 18 years, living in Nandan county, Guangxi minority region, China for at least 1 year. All participants were healthy, without any mental diseases, and were able to communicate. Eligible participants were randomly selected. The Life Event Scale Questionnaire, Simplified Coping Style Questionnaire, and Social Support Rating Scale were used to measure the physiological stress, coping style, and social support, respectively, in individuals. A total of 600 participants were recruited. A decreased risk of psychological stress was only found in TT of NPSR1 (rs324981): A allele carriers vs. TT genotype (OR 1.64, 95% CI 1.11, 2.42), and AT genotype vs. TT genotype (OR 1.76, 95% CI 1.17, 2.65). The overall coping style was positively associated with psychological stress, and no significant interactions between genetics and environment were found. We found that the NPSR1 (rs324981) T/T genotype decreased the risk of psychological stress, while the overall coping style was a risk factor for psychological stress. However, there was no interactive effects of genes and environment on psychological stress. Our findings will improve understanding of the biological basis underlying psychological stress if the results can be replicated in further research.