Vascular cognitive impairment (VCI) is a heterogeneous syndrome triggered by cerebrovascular lesions, characterized by a lack of effective treatments and complex underlying mechanisms. In this study, we investigated the neuroprotective mechanism of paeoniflorin (Pae), an active compound derived from Paeoniae Radix Alba, based on the theory of medicinal and food homology. Previous studies have identified abnormal complement system activation as a key pathological mechanism in various diseases, but its role in VCI remains unclear. To address this, we established a rat model of VCI through bilateral common carotid artery ligation (2-VO) and elucidated how paeoniflorin ameliorates cognitive deficits via modulation of the complement system. The study showed that paeoniflorin treatment improved cognitive function, alleviated WMI, reversed WMI induced MBP reduction and axonal damage, reduced microglial activation, and lowered the levels of inflammatory factors IL-6, IL-1β, and TNF-α in 2-VO rats. This indicates that paeoniflorin inhibits microglial activation and neuroinflammation. In addition, we found that paeoniflorin inhibited the activation of the C3/C3aR pathway, suggesting that it may attenuate inflammatory responses and tissue damage by modulating the activation state of the complement system. In this study, we demonstrated that the complement system is involved in VCI and concluded that paeoniflorin is a promising therapeutic candidate. For the first time, we revealed that paeoniflorin ameliorates VCI through multi-targeted regulation of the complement-microglia-myelin, providing key experimental evidence for developing neuroprotective agents based on the theory of homology of medicine and food.