Ultra-processed foods (UPFs) intake may increase cardiovascular disease (CVD) risk, but the mechanisms remain unclear and evidence on UPF biomarkers is limited. Leveraging untargeted blood metabolomics in three prospective cohorts, we identified and validated circulating metabolites associated with UPF intake and CVD risk and mortality. Discovery was conducted in the Southern Community Cohort Study (N=1,688), with validation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=2,315) and the Atherosclerosis Risk in Communities Study (N=3,682). We identified (n=142) and validated (n=43) metabolites associated with UPF intake, with several of these metabolites further linked to incident coronary heart disease (n=5), CVD mortality (n=2), and total mortality (n=20). Importantly, we developed a metabolite signature for UPF intake, which demonstrated strong associations with outcomes (OR/HR=1.25-1.46 per 1-SD increase) and explained 59-77% of the UPF-disease associations. These findings may enhance the assessment and mechanistic understanding of how UPFs impact human health.