Titanium dioxide nanoparticles (TiO NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO NPs but the underlying mechanisms are unclear at present. Data from genome-wide analyses showed that TiO NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO NP-induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO NP-induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO NP-induced ER stress occurred earlier than ROS generation. Upon treatment with 4-phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO NP increased ROS production was inhibited. These results suggest that TiO2 NP-induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO NPs on plasma glucose metabolism.