Combined with the PPI, proteomics, and western blot outcomes, we concluded that MCAO/R might induce rat cognitive deficits and cerebral infarction by inhibiting the Pak4/Akt3 and Efnb2/Akt3 pathways and that EA might ameliorate MCAO/R-induced ischemic stroke by activating the Pak4/Akt3 and Efnb2/Akt3 pathways. The gene discussed is PAK4; the disease is ischemic stroke.