Monosodium glutamate (MSG), the sodium salt of glutamic acid, is widely used in modern nutrition as flavor enhancer. However, it has been shown that curcumin has ability to induce apoptosis in the cells of the immune system. In the present study, we evaluate the potential protective effects of curcumin in MSG-induced apoptosis and signaling pathway which may be involved. Rat thymocytes were treated with increased (1, 10, 50 mM) MSG concentrations and/or curcumin (3 μM). Cell apoptosis rate, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), Bcl-2, Bax protein expression and caspase-3 activity were determined after 24 hours of incubation. Treatment with MSG resulted with increased apoptosis, ROS production and caspase-3 activity, followed with decreased MMP and Bcl-2/Bax protein ratio. Inhibition of caspase-3 and caspase-9 activity reduced cell apoptosis, indicating the involvement of mitochondrial apoptotic pathway. Co-treatment with curcumin markedly reduced apoptosis and ROS production, together with increased MMP and Bcl2/Bax protein ratio. Inhibition of PI3K/Akt signaling pathway abolished protective effect of curcumin in MSG-induced toxicity in rat thymocytes. Obtained findings suggest that curcumin may attenuate the MSG-induced apoptosis through PI3K/Akt signaling pathway which could be useful in preventing the potential deficiencies in T cell-mediated immunity.