Marek’s disease (MD) is a lymphoproliferative disease in chicken induced by Marek’s disease virus (MDV). Although some studies have focused on the genetic differences between resistant and susceptible chickens, little is known about the role of epigenetic factors in MD. In this study, genome-wide histone modifications were examined in resistant and susceptible lines of chickens. We found that tri-methylation at histone H3 Lys4 (H3K4me3) enrichment was positively correlated with the expression of protein coding genes as well as microRNA (miRNA) genes, whereas tri-methylation at histone H3 Lys27 (H3K27me3) exhibited a negative correlation. By identifying line-specific histone modifications post MDV infection, we found the unique H3K4me3 islands activated genes in the resistant chicken, which are reportedly related to immune response and cell adhesion. We also found some miRNAs from the unique H3K27me3 patterns in the susceptible chickens. The target genes of these miRNAs are involved in 5-hydroxytryptamine (5-HT)-receptor and adrenergic receptor pathways. In conclusion, dynamic line-specific histone modifications in response to MDV infection suggested that intrinsic epigenetic mechanisms may play a role in MD-resistance and -susceptibility.