Gene-environment (G × E) interactions involving job stress and mental health on risk factors of cardiovascular disease (CVD) are minimally explored. This study examined the association and G × E interaction effects of vascular endothelial growth factor receptor-2 (VEGFR-2) gene polymorphisms (rs1870377, rs2071559) on cardiometabolic risk in Chinese Malaysian adults. Questionnaires: Job Stress Scale (JSS); Depression, Anxiety, and Stress Scale (DASS-21); and Rhode Island Stress and Coping Inventory (RISCI) were used to measure job stress, mental health, and coping with perceived stress. Cardiometabolic risk parameters were evaluated in plasma and genotyping analysis was performed by real-time polymerase chain reaction. The subjects were 127 Chinese Malaysian adults. The allele frequencies for rs1870377 (A allele and T allele) and rs2071557 (A allele and T allele) polymorphisms were 0.48 and 0.52, and 0.37 and 0.63, respectively. Significant correlations include scores from JSS dimensions with blood glucose (BG) (p = 0.025-0.045), DASS-21 dimensions with blood pressure, BMI, and uric acid (p = 0.029-0.047), and RISCI with blood pressure and BG (p = 0.016-0.049). Significant G × E interactions were obtained for: rs1870377 with stress on total cholesterol (p = 0.035), low density lipoprotein cholesterol (p = 0.019), and apolipoprotein B100 (p = 0.004); and rs2071559 with anxiety on blood pressure (p = 0.006-0.045). The significant G × E interactions prompt actions for managing stress and anxiety for the prevention of CVD.