A wide plethora of intervention procedures, tissue plasminogen activators, mechanical thrombectomy, and several neuroprotective drugs were reported in stroke research over the last decennium. However, against this vivid background of newly emerging pieces of evidence, there is little to no advancement in the overall functional outcomes. With the advancement of epigenetic tools and technologies associated with intervention medicine, stroke research has entered a new fertile. The stroke involves an overabundance of inflammatory responses arising in part due to the body's immune response to brain injury. Neuroinflammation contributes to significant neuronal cell death and the development of functional impairment and even death in stroke patients. Recent studies have demonstrated that epigenetics plays a key role in post-stroke conditions, leading to inflammatory responses and alteration of the microenvironment within the injured tissue. In this review, we summarize the progress of epigenetics which provides an overview of recent advancements on the emerging key role of secondary brain injury in stroke. We also discuss potential epigenetic therapies related to clinical practice.