© Copyright © 2019 Shah, Li, Kury, Zeb, Khatoon, Liu, Yang, Liu, Yao, Khan, Koh, Jiang and Li. Ischemic strokes are categorized by permanent or transient obstruction of blood flow, which impedes delivery of oxygen and essential nutrients to brain. In the last decade, the therapeutic window for tPA has increased from 3 to 5–6 h, and a new technique, involving the mechanical removal of the clot (endovascular thrombectomy) to allow reperfusion of the injured area, is being used more often. This last therapeutic approach can be done until 24 h after stroke onset. Due to this fact, more acute ischemic stroke patients are now being recanalized, and so tMCAO is probably the “best” model to address these patients that have a potential good outcome in terms of survival and functional recovery. However, permanent occlusion patients are also important, not only to increase survival rate but also to improve functional outcomes, although these are more difficult to achieve. So, both models are important, and which target different stroke patients in the clinical scenario. Hippocampus has a vital role in memory and cognition, is prone to ischemic induced neurodegeneration. This study was designed to delineate the molecular, pathological, and neurological changes in rat models of t-MCAO, permanent MCAO (pMCAO), and pMCAO with diabetic conditions in hippocampal tissue. Our results showed that these three models showed distinct discrepancies at numerous pathological process, including key signaling molecules involved in neuronal apoptosis, glutamate induced excitotoxicity, neuroinflammation, oxidative stress, and neurotrophic changes. Our result suggests that the two commonly used MCAO models exhibited tremendous differences in terms of neuronal cell loss, glutamate excitotoxic related signaling, synaptic transmission markers, neuron inflammatory and oxidative stress molecules. These differences may reflect the variations in different models, which may provide valuable information for mechanistic and therapeutic inconsistences as experienced in both preclinical models and clinical trials.