Post-stroke cognitive impairment (PSCI) is a common complication following a stroke, affecting life quality of stroke survivors and their rehabilitation outcomes. Yet, the mechanism underlying PSCI is not fully understood. Our previous study showed that upregulation of autophagy in neurons preluded the disruption of the synaptic ultrastructures after acute cerebral ischemia via the impairment in the turnover of synaptic proteins. However, the upstream signaling of upregulation of autophagy and whether this disrupted synaptic proteostasis is vital for PSCI is still required to be explored. Here, we sought that the protein level of TAK1 was increased significantly in neurons by oxidative stress upon acute ischemia and bridged the redox stress with the autophagy upregulation via interacting with PP2A-C although TAK1 is not the component of the core conserved atg genes in autophagic machinery or the main regulatory machinery mediated by mTOR signaling. Moreover, the intervention of TAK1 did not influence the basal performance of autophagy machinery and synaptic homeostasis under normoxia condition. Of note, TAK1-targeted treatment improved the synaptic ultra-structures and cognitive behaviors of MCAO mice via facilitating their synaptic proteostasis, exhibiting superiority over the outcomes experiencing ATG7-targeted treatment. Overall, our study demonstrates that redox stress induced by cerebral ischemia may turn on the alternative regulatory pathway of autophagy via TAK1 signaling in neurons, preluding disrupted synaptic proteostasis and then PSCI.