Resveratrol offers pleiotropic health beneficial effects including its reported capability to inhibit lipopolysaccharide (LPS) induced cytokine production. The aim of this work was to prepare, characterize and evaluate a resveratrol nanoparticulate formulation based on zein. For this purpose the oral bioavailability of the encapsulated polyphenol as well as its anti-inflammatory effect in a mouse model of endotoxic shock were studied. Resveratrol-loaded nanoparticles displayed sizes around 300 nm with a negative zeta potential (- 51 mV) and a polyphenol loading close to 80 μg/mg. In vitro, the release of resveratrol from the nanoparticles was found to be pH-independent and adjusted well to the Peppas-Salin kinetic model, suggesting a mechanism based on the combination between diffusion and erosion of the nanoparticle matrix. Pharmacokinetic studies demonstrated that zein-based nanoparticles provided high and prolonged plasma levels of the polyphenol for at least 48 h. The oral bioavailability of resveratrol when administered in these nanoparticles increased up to 50% (20-fold higher than for the control solution of the polyphenol). Furthermore, nanoparticles administered daily for 7 days at 15 mg/kg, were able to diminish the endotoxic symptoms induced in mouse by the ip administration of LPS (i.e. hypothermia, piloerection and stillness). In addition, serum TNF-α levels were slightly lower (about 15%) of those observed for the control.