Mastitis is a major health and economic threat to the dairy industry, causing massive losses every year worldwide. Staphylococcus aureus is the chief pathogen responsible for most of the subclinical as well as a considerable portion of the clinical cases. Conventional control strategies, including antibiotic treatment and genetic selection for resistance, have limited success due to antimicrobial resistance (AMR) and low heritability of mastitis susceptibility. This calls for the exploration of novel approaches like epigenetics, which offers insights into host-pathogen interactions beyond the genetic variations. This review focuses on DNA methylation changes in the mammary gland that occur during S. aureus mastitis. Recent research works have identified immune suppression and pathogen persistence in relation with DNA methylation during the disease. The microbe has been reported to alter the methylation status of regulatory regions for many immune genes like CXCR1, TNF-α, IL6R, IL10, and C3, resulting in dysregulation of immune responses in the host, and thereby facilitating pathogen persistence and chronic infection. Along with its own virulence factors, differential DNA methylation status of such genes during infection helps the pathogen to escape host defence, and decreases the intensity of inflammation. Thus, understanding these mechanisms can open new avenues in the field of disease detection, animal selection, and immunotherapy among others. Such an integrative approach offers a revolutionization of mastitis control strategies, ensuring better health and productivity in dairy animals.