3-Hydroxykynurenine (3-HK), which is an endogenous metabolite of tryptophan in the kynurenine pathway, is a potential neurotoxin in several neurodegenerative disorders. Epigallocatechin 3-gallate (EGCG), a major compound of green tea, is recognized as a promising natural substance for protection against neuronal diseases. This study investigated the possible protective roles and mechanism of EGCG, against 3-HK-induced cell death. It was found that 3-HK induces neuronal cell death in the human neuroblastoma SH-SY5Y cell line. The reduced cell viability produced characteristic features such as cell shrinkages, plasma membrane blebbing, chromatin condensation, and nuclear fragmentation. The cells treated with 3-HK showed an increase in the concentration of reactive oxygen species (ROS) as well as in caspase activity. In addition, both are involved in the 3-HK-induced apoptosis. EGCG attenuated the cell viability reduction by 3-HK in both a dose- and time-dependent manner. Optical microscopy showed that EGCG inhibited the cell morphological features in the 3-HK-treated cells. Furthermore, the increase in the ROS concentration and the caspase activities by 3-HK were also attenuated by EGCG. These results showed that EGCG has a protective effect on the 3-HK induced cell death by inhibiting ROS production and caspase activity. The results suggest that EGCG might be a promising protective substance against the neuronal degenerative diseases.