ZnO and ZnO nanoparticles (ZnO NPs) are widely used in food packaging, food preservation, cosmetic preparation, and animal feed. ZnO is alleged showing multiple bioactivities including antimicrobial and anti-inflammation. It is hypothesized in this study that bulk ZnO and ZnO NPs could attenuate symptoms associated with high-fat-diet-induced obesity. Bulk ZnO and ZnO NPs with diameters of 30 and 90 nm were administered to high-fat-diet (HFD)-induced obese mice. Body weight, liver and fat tissue indices of ZnO-treated mice were decreased compared with those of obese mice (MOD). Blood glucose levels in oral glucose tolerant test and insulin tolerant test of ZnO-treated mice were lower than those of MOD. Serum lipid profile of ZnO-treated mice was ameliorated with lower total cholesterol, total triglyceride, and low-density lipoprotein cholesterol levels compared with that of MOD. In addition, the levels of serum IL-1 beta and LPS-binding protein were also decreased by ZnO treatment. Both bulk and nanosized ZnO could attenuate HFD-induced phenotypes related with obesity, but ZnO NP is more efficient to lower the fat index and bulk ZnO is better to restore the disturbed serum lipid profile.