Astroviruses are a common cause of gastrointestinal disease in humans and have been recognized to cause fatal cases of encephalitis. A major barrier to the study of human-infecting astroviruses is the lack of an in vivo model, as previous attempts failed to identify a suitable host that supports viral replication. We describe a novel murine model of infection using astrovirus VA1/HMO-C (VA1), an astrovirus with high seroprevalence in humans that is a causative agent of encephalitis. VA1 RNA levels peak in heart tissue at day 7 post-inoculation. The cardiotropism was observed in multiple different murine genetic backgrounds evidenced by high VA1 RNA loads in heart tissue of A/J, C57BL/6, C3H/HeJ, Balb/c, and J:ARC mice. Infectious VA1 particles could be recovered from heart tissue 3 and 5 days post-inoculation. Intracellular viral capsid was present in tissue sections based on immunofluorescent staining and viral RNA was detected in cardiac myocytes, endocardium, and endothelial cells based on fluorescent in situ hybridization and confocal microscopy. Histologically, we identified inflammatory infiltrates consistent with myocarditis in some mice, with viral RNA co-localizing with the infiltrates. These foci contained CD3+ T cells and CD68+ macrophages. Viral RNA levels increased by > 10-fold in heart tissue or serum samples from Rag1 or Stat1 knockout mice, demonstrating the role of both adaptive and innate immunity in the response to VA1 infection. Based on the in vivo tropisms, we also tested cardiac-derived primary cells and determined that VA1 can replicate in human cardiac microvascular and coronary artery endothelial cells, suggesting a novel cardiovascular tropism in human cells. This novel in vivo model of a human-infecting astrovirus enables further characterization of viral pathogenesis and reveals a new cardiovascular tropism of astroviruses.