Stroke, the third leading cause of death and disability worldwide, is evolving with new insights into neurodegeneration. The concept that stroke is solely a vascular disorder has expanded to include detrimental interactions between glia, neurons, vascular cells, and matrix components, collectively referred to as the neurovascular unit. Following ischemic stroke, secondary neuroinflammation promotes further injury and cell death but also plays a beneficial role in recovery. Pro-inflammatory signals from immune mediators activate resident cells and influence the infiltration of various inflammatory cells (neutrophils, monocytes/macrophages, T cells, and others) into the ischemic region, exacerbating brain damage. This review discusses the dual roles of neuroinflammation and recent therapeutic strategies to combat pathological responses. It focuses on the time-dependent entry of immune cells into the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications, which can perpetuate ischemic brain damage after acute injury. Understanding the time-dependent role of inflammatory factors could help develop new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.Stroke, the third leading cause of death and disability worldwide, is evolving with new insights into neurodegeneration. The concept that stroke is solely a vascular disorder has expanded to include detrimental interactions between glia, neurons, vascular cells, and matrix components, collectively referred to as the neurovascular unit. Following ischemic stroke, secondary neuroinflammation promotes further injury and cell death but also plays a beneficial role in recovery. Pro-inflammatory signals from immune mediators activate resident cells and influence the infiltration of various inflammatory cells (neutrophils, monocytes/macrophages, T cells, and others) into the ischemic region, exacerbating brain damage. This review discusses the dual roles of neuroinflammation and recent therapeutic strategies to combat pathological responses. It focuses on the time-dependent entry of immune cells into the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications, which can perpetuate ischemic brain damage after acute injury. Understanding the time-dependent role of inflammatory factors could help develop new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.