High levels of homocysteine (Hcy) were shown to be a significant independent risk factor for some neurological diseases. Such a condition induces excessive production of reactive oxygen species (ROSs) in human glioma cells. Curcumin, an active component of turmeric (Curcuma longa), provides strong antioxidant effects in in vitro and in vivo experimental models. However, mechanisms of the effect of curcumin against Hcy-induced cell damage have not yet been elucidated in detail. This study investigated whether curcumin can protect cultured U373 glioblastoma cells against Hcy-induced damage, and what are probable cellular mechanisms of this effect, namely, alterations in the expressions of a transcription factor (nuclear E2-related factor-2, Nrf2), hemoxygenase 1 (HO-1), and TP53-induced glycolysis and apoptosis regulator (TIGAR). The results showed that curcumin partially enhanced cell viability of Hcy-treated cells and significantly attenuated intracellular ROS formation. Pretreatment of curcumin also partially moderated Hcy-induced oxidative damage via HO-1 expression through activating Nrf2 expression. Furthermore, TIGAR also contributed to the protective effect of curcumin against cell damage caused by Hcy in the U373 cell line. Taken together, these results indicate that modulation of the Nrf2/HO-1 signal pathway and TIGAR expression can play a pivotal role in the protective effects of curcumin against Hcy-induced oxidative damage in glial cells.