Individuals reporting the highest intake of UPF (Q4, >14.6% of total food), as opposed to the lowest (Q1, UPF < 6.6%), experienced increased risks of CVD mortality (HR: 1.58; 95% CI: 1.23, 2.03), death from ischemic heart disease (IHD)/cerebrovascular disease (HR: 1.52; 95% CI: 1.10, 2.09), and all-cause mortality (HR: 1.26; 95% CI: 1.09, 1.46). High sugar content explained 36.3% of the relation of UPF with IHD/cerebrovascular mortality, whereas other nutritional factors (e.g., saturated fats) were unlikely to be on the pathway. Biomarkers of renal function accounted for 20.1% of the association of UPF with all-cause mortality, and 12.0% for that of UPF with CVD mortality. Conclusions: A high proportion of UPF in the diet was associated with increased risk of CVD and all-cause mortality, partly through its high dietary content of sugar. Some established biomarkers of CVD risk were likely to be on the pathway of such associations. These findings should serve as an incentive for limiting consumption of UPF, and encouraging natural or minimally processed foods, as several national nutritional policies recommend.