Abundant evidence has correlated influenza infection with cardiovascular disease, yet mechanisms linking infection with the heart remain poorly understood. Here, we show that influenza infection damaged the human and murine heart. In mice, we showed that shortly after pulmonary infection, the virus infected a circulating myeloid pro-dendritic cell 3 (pro-DC3) that expressed high concentrations of the chemokine receptor CCR2. The heart, which produces abundant CCL2, preferentially attracted infected pro-DC3. In the myocardium, the virus escaped pro-DC3, infected cardiomyocytes, and triggered production of type-I interferon (IFN-I). Engagement of the IFN-I receptor (IFNAR1) on cardiomyocytes caused tissue damage and compromised heart function. Genetically and therapeutically dampening IFNAR1 exclusively in cardiomyocytes protected the heart while preserving anti-viral immunity in the lung. Our results identify a series of host-pathogen interactions that propagate tissue damage and uncover an axis for intervention to mitigate cardiovascular risk following viral infection.