This investigation evaluated the neuroprotective effect of melodinhenine B in a cerebral ischemia/reperfusion (I/R)-induced neuronal injury rat model. The effect of melodinhenine B was determined by evaluating the neurological deficit score, cerebral infarcted area, and blood-brain barrier (BBB) permeability. Moreover, the level of inflammatory cytokines and expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ), interleukin-1β (IL-1β), NLRP3, zonula occludens-1 (ZO-1), and occluding proteins were estimated by Western blotting. Histopathological changes and immunohistochemical analysis were performed to estimate the effect of melodinhenine B on neuronal injury. The neurological deficit score, percentage of infarcted area, and BBB permeability were improved in the melodinhenine B-treated group of rats. Treatment with melodinhenine B attenuated the altered expression of NF-κβ, IL-1β, NLRP3, ZO-1, and occluding proteins in the brain tissue of I/R-induced neuronal injury rats. The inflammatory cytokine levels were reduced in the melodinhenine B-treated group. Histopathologically, melodinhenine B reversed the pathological changes in the brain tissues of I/R-induced neuronal injury rats. In conclusion, melodinhenine B protects against neuronal injury in cerebral ischemia-reperfusion injury rats by regulating the inflammasomes.