Vascular dementia (VaD) is one of the most common clinical syndromes of progressive neurocognitive dysfunction with uncertain mechanisms. Modified Erchen decoction (MECD), developed from "Erchen decoction (ECD)" recorded in "Taiping Huimin Heji Jufang", showed a good effect in the treatment of VaD. However, its therapeutic mechanism is still unclear.This study aimed to elucidate the multi-target mechanisms of MECD against VaD in vivo and in vitro.VaD model was established by two-vessel obstruction (2-VO) in Sprague-Dawley rats. Six groups, including the control, 2-VO operation, MECD treatment (2.5, 5.0 and 10.0 g kg-1 d-1), donepezil hydrochloride (positive control, 0.45 g kg-1 d-1) were designed in the whole experiment. After oral administration for 4 weeks, the effects of MECD were verified by behavioral experiments, histological observation, and biochemical index analysis. The chemical profiling of MECD was performed by UHPLC-Orbitrap Fusion-HRMS, and a "compound-target-pathway" multivariate network was constructed to validate and elucidate its pharmacological mechanisms.Compared with 2-VO group, MECD treatment significantly alleviated anxiety and improved spatial memory in VaD rats according to the open field test (OFT) and Y-maze test. A significant increase in neuron number was observed from hematoxylin and eosin (H&E) stained images in cornu ammonis 1 (CA1) of the hippocampal region after MECD treatment. On the one hand, MECD reduced the plasma levels of triglyceride (TG), low-density lipoprotein (LDL), malondialdehyde (MDA), and amyloid-beta 42 (Aβ42), and inhibited mRNA expression of interleukin-1 beta (Il-1β) and Il-6 in the hippocampus. On the other hand, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly increased after treatment with MECD. Moreover, MECD reduced the mRNA expression and protein expression of janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and BCL2-associated X (BAX) in the brain of 2-VO rats. Furthermore, 71 compounds were identified from the extract of MECD. Among them, liquiritin and isochlorogenic acid C gave inhibiting effects on the mRNA expression of Jnk. In addition, liquiritin and hesperetin were conformed with the inhibition of Jak2 transcription level in vitro experiments.MECD has demonstrated a significant amelioration effect on cognitive dysfunction in VaD rats via JAK2/STAT3 and JNK/BAX signaling pathways, which represents an innovative insight into the "activate blood and eliminate phlegm" theory.Copyright © 2023 Elsevier GmbH. All rights reserved.