Background Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4(+) T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4(+) T cell senescence and identified the underlying mechanisms using a d-gal-induced mouse aging model. Methods In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, d-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4(+) T (CD4CD45RA) cells were prepared using a naive CD4(+) T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4(+) T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-beta-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy. Results We found that hPMSC treatment markedly decreased the ROS level, SA-beta-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4(+) T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4(+) T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4(+) T cell senescence by upregulating the Akt/GSK-3 beta/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4(+) T cells. Conclusions Our results indicate that hPMSCs attenuate d-gal-induced CD4(+) T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3 beta/Fyn pathway.