The important therapeutic role of melatonin in neuropathological conditions is underscored by a broad array of studies, many of which elucidated its neuroprotective properties. Yet, our scientific knowledge still needs several approaches to uncover molecular mechanisms. In this study, we contextually modelled cerebral ischemia through transient intraluminal middle cerebral artery occlusion. Melatonin was administered via an intraperitoneally placed mini osmotic pump, and released periodically from 3 days post-ischemia (dpi) to 56 dpi. We conferred several lines of evidence to address the fundamental questions about melatonin’s cytoprotective functions after cerebral ischemia. We demonstrated that melatonin assisted post-ischemic neuro-restoration and micro-vascularization. In addition, it restricted glial scar formation, which interferes with neuronal interactions and stands as a barrier against plasticity. Even more interestingly, axonal plasticity, which was studied on the pyramidal tract using an anterograde tract tracer, proved the role of melatonin in remodeling across the injury site. In addition, plasticity-associated membrane-localized proteins, ephrin b1, ephrin b2, brevican, and versican were also modulated by melatonin. These findings suggested that melatonin orchestrated neurological recovery which was accompanied by molecular alterations resulting in cellular and extracellular structural changes. Based on the molecular signatures, ipsilesional and contralesional brain tissues were finely tuned by melatonin to compensate the loss after ischemia. Accordingly, neurological improvements correlated with the brain’s molecular changes over time. It was suggested that melatonin enabled neuronal recovery by regulating neurogenesis and neuroplasticity in long term.