A system-wide cardiovascular response to traffic-related air pollution (TRAP) has been rarely described. To systemically understand the mechanisms underlying cardiovascular effects of TRAP, we conducted a randomized, crossover trial in 56 young adults, who engaged in two 4-hour exposure sessions on a main road and in a park, alternately. We measured personal exposures to traffic-related air pollutants (TRAPs), including fine and ultrafine particulate matter, black carbon, nitrogen dioxide, and carbon monoxide. Lipidomics, targeted proteomics, urine metabolomics, targeted biomarkers, ambulatory blood pressure and electrocardiogram were measured. We used linear mixed-effects models to estimate the associations. The exposures to TRAPs except for fine particulate matter in the road session were 2-3 times higher. We observed elevated blood pressure and decreased heart rate variability (HRV) after TRAP exposure, accompanied by dozens of molecular alterations involving systemic inflammation, oxidative stress, endothelial dysfunction, coagulation, and lipid metabolism. Pathways like vascular smooth muscle cell proliferation and biomarkers like trimethylamine N-Oxide might also be disturbed. Some of these TRAP-related molecular biomarkers were also associated with changes of blood pressure or HRV. Our results provided systematical mechanistic profiling for the cardiovascular effects of TRAP using multi omics, which may have implications in TRAP control.