Depression commonly coexists with cardiovascular disease (CVD) and worsens prognosis, yet uncertainty persists about the efficacy and cardiovascular safety of antidepressants in cardiac populations. Following PRISMA 2020 guidelines, we systematically reviewed randomized controlled trials (RCTs) in English that contained Food and Drug Administration-approved antidepressant with at least one cardiovascular outcome (primary, secondary, or safety). Dual screening, extraction, and outcome-level risk of bias (RoB 2) were performed, and certainty was graded with GRADE. Heterogeneity in outcomes precluded meta-analysis and was summarized qualitatively. Seven RCTs (N = 3,512; mean age 58–67 years) met criteria. Results showed that selective serotonin reuptake inhibitors (SSRI) were CVD-neutral versus placebo/usual care, no excess in major adverse cardiovascular events (MACE), arrhythmia, QTc prolongation, or mortality. Antidepressant efficacy results were mixed with sertraline not outperforming placebo in heart failure, whereas escitalopram prevented incident depression post-acute coronary syndrome. A head-to-head trial showed that nortriptyline had more cardiac adverse events than paroxetine, supporting avoidance of tricyclics in ischemic heart disease. Integrated models showed dual benefits where older adults markedly improved depression and tripled hypertension control and those without baseline CVD had reduced long-term myocardial infarction or stroke. Overall, GRADE certainty score was higher for SSRI cardiovascular safety than for antidepressant efficacy, limited by modest sample sizes, outcome heterogeneity, and short follow-up. SSRIs appear cardiologically safe in adults with CVD in short term, tricyclics should generally be avoided, and early, collaborative depression care may yield cardiometabolic benefits, especially before overt CVD. Finally, large, longer-term RCTs with prespecified MACE and bleeding/QTc endpoints are needed to refine efficacy estimates.