BACKGROUND: Depression is linked to major adverse cardiac events (MACE), yet the role of stress-related neural activity–previously implicated in stress and anxiety—in mediating this association remains unclear. Because anxiety and depression frequently co-occur and share neurobiological pathways, we hypothesized that the relationship between depression, anxiety, and their co-occurrence with MACE is partially mediated by increased stress-related neural activity and related autonomic-immune mechanisms. METHODS: Data were obtained from participants enrolled in the Mass General Brigham Biobank (2010–2020). A subset underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography imaging to assess stress-related neural activity, defined as the ratio of amygdala to background prefrontal cortical activity. Heart rate variability and CRP (C-reactive protein) served as indicators of autonomic activity and systemic inflammation. Depression and anxiety were determined at enrollment, and MACE was identified during follow-up using International Classification of Diseases codes. Each exposure (depression, anxiety, or concurrent anxiety plus depression) was modeled separately against study outcomes using linear and Cox regressions. RESULTS: Of 85 551 study subjects, 3078 (3.6%) participants developed MACE, over a median 3.4 years follow-up (interquartile range, 1.9–4.8). Depression was associated with higher MACE risk (hazard ratio, 1.24 [95% CI, 1.14–1.34]; P <0.001), with stronger associations for concurrent anxiety plus depression (hazard ratio, 1.35 [1.23–1.49]; P <0.001) and remained significant after adjustment for demographics, lifestyle, cardiovascular, and socioeconomic factors. In subsamples with available imaging (N=1123) or biomarkers (heart rate variability, N=7862; CRP, N=12 906), depression was linked to higher amygdala-to-cortex activity ratio (β=0.16; P =0.006), lower heart rate variability (β=−0.20; P <0.001), and higher CRP (β=0.14; P <0.001). Mediation analyses showed indirect effects of amygdala-to-cortex activity ratio, heart rate variability, and CRP on the depression–MACE relationship (log odds ratios, 0.04, 0.04, and 0.02, respectively; all P <0.05). Similar associations were observed for anxiety or concurrent anxiety plus depression. CONCLUSIONS: Depression and anxiety independently associate with increased MACE risk, partly mediated by heightened stress-related neural activity and autonomic-immune dysregulation. The risk is greatest among those with both conditions, underscoring shared stress-related pathophysiology.