Ischemic stroke triggers a cascade of oxidative stress, neuroinflammation, and synaptic dysfunction, leading to long-term cognitive and motor deficits. The human dental pulp stem cell (hDPSC) secretome, derived from neural crest-origin cells, has emerged as a promising cell-free therapeutic candidate due to its composition of neurotrophic, antioxidant, and immunomodulatory factors. In this study, we demonstrate that hDPSC secretome exerts neuroprotective effects in both a photothrombotic mouse model of ischemic stroke and CoCl₂-induced hypoxic BV2 microglial cells. Proteomic analysis revealed that the hDPSC secretome contains key antioxidant enzymes (SOD2, GSR, and GSTP1) and M2 microglial inducers (GRN, CSF1, and LRP1), which reduce neuronal ROS levels and promote anti-inflammatory microglial polarization. Furthermore, the hDPSC secretome enhanced neurogenesis and angiogenesis in the hippocampus and cortex, and restored synaptic structure and function by upregulating calcium signaling and ROBO–Rho pathway-associated synaptic proteins. These molecular and cellular effects translated into significant recovery of stroke-induced cognitive deficits, including improved memory and spatial learning, reduced anxiety-like behavior, as indicated by improved stress response, and enhanced motor function, reflected in improved coordination and balance. Together, these findings support the therapeutic potential of hDPSC secretome to promote brain repair after ischemic stroke by re-establishing redox balance, suppressing inflammation, and enhancing synaptic plasticity.