Phenylethanoid glycosides derived from Cistanche deserticola (PhGs) are plant-derived natural medicinal compounds that occur in many medicinal plants. This study aims to investigate whether PhGs treatment improves the stroke and its potential mechanisms. Adult male C57BL/6 J mice were administrated PhGs once daily for 7 days after MCAO surgery. The neurological score, and catwalk were evaluated on Day 1, 3 and 7 after ischemic stroke. Furthermore, triphenyl-2,3,5-tetrazoliumchloride (TTC) and hematoxylin-eosin (H & E) staining were used for evaluating the infarct volume and neuronal restoration. The effects of PhGs on NSCs proliferation were investigated in vitro and in vivo . Western blot was used to detect the proteins of Wnt/β-catenin signaling pathway. This study found that PhGs effectively improved the neurological functions in ischemic stroke mice. TTC and H & E staining demonstrated that PhGs not only reduced infarct volume, but also improved neuronal restoration. The immunohistochemistry and 5-Ethynyl-2-deoxyuridine (EdU) incorporation assays revealed that PhGs promoted the proliferation of neural stem cells (NSCs) in subventricular zone (SVZ). In addition, transcriptome analysis of NSCs showed that the Wnt/β-catenin signaling pathway was involved in the PhGs induced NSCs proliferation. Importantly, the related proteins in the Wnt/β-catenin signaling pathway were changed after PhGs treatment, including β-catenin, Wnt3a, GSK-3β, c-Myc. PhGs treatment improved the stroke through enhancing endogenous NSCs proliferation via activating Wnt/β-catenin signaling pathway. Due to its effect on the proliferation of NSCs, PhGs are a potential adjuvant therapeutic drug for post-stroke treatment.