Lower socioeconomic status (SES) and higher neuroticism polygenic risk score (NEU-PGS) associate with cardiovascular disease (CVD). Chronic stress increases CVD risk via activation of neural, autonomic, and immune pathways. We evaluated whether 1) higher NEU-PGS accentuates the association between lower SES and major adverse cardiovascular events (MACE); and 2) higher stress-associated neural activity and C-reactive protein and lower heart rate variability contribute to the SES-MACE link among those with higher NEU-PGS. NEU-PGS (from those with European ancestry) and SES data were derived from individuals in the Mass General Brigham Biobank. SES was assessed as median household income (N = 18,093) and area deprivation index (ADI, N = 15,276). Lower household income was defined as the lowest tertile and higher ADI as the highest. NEU-PGS was stratified about the population median. MACE, stress-associated neural activity, heart rate variability, and C-reactive protein were assessed from clinical data. Among individuals with higher (but not lower) NEU-PGS, lower household income associated with MACE (N = 6,574; OR: 1.22, p = 0.005), stress-associated neural activity (N = 480; standardized β: 0.14, p = 0.003), and heart rate variability (1,361; -0.05, p = 0.041). Higher ADI associated with MACE (5,441; 1.24, p = 0.008) and heart rate variability (1,127; -0.09, p = 0.001) among those with higher (but not lower) NEU-PGS. Lower SES associated with higher C-reactive protein across NEU-PGS groups. The mediating effect of stress-associated neural activity, heart rate variability and C-reactive protein in the SES-MACE relationship was moderated by higher NEU-PGS. Individuals with higher NEU-PGS experience greater CVD risk related to lower SES via alterations in neural, autonomic, and immune mechanisms.