<p>Stroke is one of the leading causes of disability and mortality worldwide, with ischemic stroke representing the most prevalent and devastating form. This review offers an in-depth exploration of the critical role of N-Methyl-D-Aspartate Receptor (NMDAR) signaling in mediating the brain's response to ischemic injury. NMDAR activation triggers glutamate excitotoxicity, setting off a cascade of neurotoxic events that lead to mitochondrial dysfunction and the generation of reactive oxygen species (ROS). These damaging processes not only intensify neuronal injury but also activate apoptotic pathways, including p53-mediated and Notch signaling. Furthermore, the review highlights necroptosis as a key cell death mechanism in ischemic injury and examines the subsequent disruption of the blood–brain barrier (BBB), which exacerbates brain damage. In the context of neuroprotective signaling, we explore the distinct roles of synaptic and extrasynaptic NMDAR activation, neurotrophic factor-mediated signaling, and the intricate crosstalk between neurotoxic and neuroprotective pathways. This review also explores novel hypotheses and emerging perspectives in NMDAR-mediated ischemic stroke, highlighting potential mechanisms and therapeutic implications. Additionally, it covers cutting-edge experimental approaches to investigate NMDAR function in stroke and provides critical insights into conflicting findings in NMDAR research, addressing key controversies and their impact on future studies. Therapeutic strategies targeting ischemic stroke are critically examined, with an emphasis on potential interventions that could mitigate the effects of ischemia. The review also highlights ongoing clinical trials investigating novel therapeutic approaches and outlines the future direction of ischemic stroke therapy. This comprehensive review offers a deep understanding of the complex molecular mechanisms involved in ischemic stroke via NMDAR and provides valuable insights into the promising therapeutic avenues that could lead to more effective treatments.</p> Graphical abstract <p></p>