Avian influenza has caused significant damage to the poultry industry globally. Consequently, efforts have been made to elucidate the disease mechanisms as well as the mechanisms of disease resistance. Here, by investigating two chicken breeds with distinct responses to avian influenza virus (AIV), Leghorn GB2 and Fayoumi M43, we compared their genome, methylation, and transcriptome differences. MX1, HSP90AB1, and HSP90B1 exhibited high degrees of genetic differentiation (FST) between the two species. Except for the MX1-involved direct anti-virus mechanism, we found that at the methylation and transcriptome levels, the more AIV-resistant breed, Fayoumi, exhibited less variation compared with Leghorn after AIV inoculation, which included change trends in differentially expressed regions, top-fold change genes with FDR-corrected p < 0.05, immune response related genes, and housekeeping genes. Fayoumi also showed better consistency regarding changes in methylation and changes at the transcriptome level. Our results suggest a homeostasis hypothesis for avian influenza resistance, with Fayoumi maintaining superior homeostasis at both the epigenetic and gene expression levels. Three candidate genes-MX1, HSP90AB1, and HSP90B1-showed genetic differentiation and altered gene expression, methylation, and protein expression, which merit attention in further functional studies.