Despite the wealth of information on viral hepatitis in people, the role of viruses in equine liver disease is just starting to be explored. It wasn’t until the development and application of unbiased next generation sequencing that putative hepatitis viruses of horses were first described. I carried out a series of in vivo studies to characterize the two recently discovered equine hepatitis viruses, Equine parvovirus-hepatitis (EqPV-H) and Equine hepacivirus (EqHV). First, I present the state of knowledge for equine hepatitis viruses to provide the context for the following studies. Second, I present the use of single cell RNA-sequencing to establish an atlas of equine peripheral blood mononuclear cell (PBMC) subtypes and to validate a flow cytometric phenotyping panel used in the following studies. This overcame a major hurdle in studying the immune responses in a non-traditional model organism: the lack of baseline knowledge of PBMC populations and proportions. For Equine parvovirus-hepatitis, I assessed the role of EqPV-H infection in liver disease. Earlier case studies had shown an association between EqPV-H infection and Theiler’s disease, or acute hepatic necrosis. A series of in vivo experimental infections showed that EqPV-H is hepatotropic and that seroconversion and a decline in viremia are consistently associated with hepatitis, indicating a causal relationship. Finally, EqPV-H infection via allogenic stem cell injections and oral administration demonstrated transmission by iatrogenic and natural routes. For Equine hepacivirus, I assessed the immunopathology of EqHV and similarities to human infection with the closely related virus, hepatitis C virus (HCV). During experimental infections, local interferon-stimulated gene signatures in the liver and functional sequestration of micro-RNA-122 were observed. EqHV infection typically had an acute resolving course, and horses had a higher rate of hepaciviral clearance than humans. The protective immune response lasted for at least a year and broadly attenuated subsequent infections. This could have important implications to achieve the primary goal of HCV vaccines; to prevent chronicity while accepting acute resolving infection after virus exposure. Equine parvovirus-hepatitis and Equine hepacivirus are significant equine liver pathogens. These results indicate future studies are warranted to develop management and treatment strategies for these conditions in horses.