Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation is a promising therapy for Alzheimer's disease (AD). However, hUC-MSCs cultured in vitro easily exhibit replicative senescence, which restricts their application. Although MG53 protein demonstrates multiple roles for a variety of cells and tissues repair, it remains unknown whether MG53 could rejuvenate senescent hUC-MSCs and enhance their efficacy in AD model. Here, we firstly presented that MG53 reinstated senescent hUC-MSCs via the activation of the Nrf2 signaling pathway by increasing cell proliferation and migration, ameliorating senescence and oxidative stress, and decreasing the release of senescence-associated secretory phenotype. In vivo studies showed that MG53 treatment improved the therapeutic effect of senescent hUC-MSCs in AD mice. Furthermore, MG53 combined with young hUC-MSCs transplantation alleviated cognitive deficit and depression-like behavior in AD mice, reduced Aβ deposition and Tau phosphorylation, promoted neurogenesis, and inhibited glia cells activation and oxidative stress by activating the Nrf2 signaling. Moreover, these neuroprotective effects mediated by MG53 and hUC-MSCs were partly reversed by Brusatol, a specific inhibitor of Nrf2 signaling. Taken together, our study revealed that MG53 could rejuvenate senescent hUC-MSCs and facilitate their efficacy in AD mice at least partly through activating Nrf2 signaling pathway, which suggest that the combined therapy of MG53 and hUC-MSCs may be a novel and effective strategy for AD.