Vascular dementia (VaD) is associated with cerebral hypoperfusion, which results in long-term cognitive impairment and memory loss. Cornel iridoid glycoside (CIG) is the major active constituent isolated from the ripe fruit of Cornus officinalis. Previous studies have shown that CIG enhances neurological function in VaD rats. In the present research, we attempted to clarify the molecular processes underlying the role of CIG in neuroinflammation in VaD. We created a chronic cerebral ischemia rat model by ligation of the bilateral common carotid arteries (2VO) and then treated rats with different concentrations of CIG. Comprehensive analyses revealed that CIG ameliorated myelin integrity and neuronal loss. Furthermore, we also found that CIG inhibited polarized microglia activation and attenuated inflammasome-mediated production of proinflammatory cytokines in BV2 microglia cells induced by LPS/IFN-γ and in the brains of 2VO rats. To further elucidate the role of CIG in microglia-mediated inflammatory response, we investigated the expression and activity of calpain. CIG inhibited the expression and activity of calpain 1/2, which was characterized by decreased calpastatin and spectrin αII expression. In particular, intra- and extracellular calpain 1 levels were reduced by CIG. However, CIG showed weak interaction with calpain 1. In addition, we found that CG administration significantly repressed the assembly of the NOD-like receptor protein 3 (NLRP3) inflammasome, including NLRP3, ASC, and caspase-1. In conclusion, our knowledge of the mechanisms by which CIG regulates NLRP3/calpain signaling to influence inflammatory responses offers further insights into potential therapeutic strategies to treat VaD.