Quercetin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Qu-NP) were prepared by emulsion-diffusion-evaporation method and characterized as 179.9 ± 11.2 nm in size with 0.128 as polydispersity index, more than 86% drug entrapment efficiency, and zeta potential was -6.06 ± 1.51 mV. D-Trehalose (5% w/v) was found to be a suitable cryoprotectant for lyophilization of Qu-NP, and antioxidant assays indicated that Qu-NP were able to retain the antioxidant property similar to that of free drug at equivalent concentration after formulation development. In vitro release study of Qu-NP showed a controlled release pattern of quercetin. An enhanced oral bioavailability (523% relative increase) was observed in pharmacokinetic study with a 6-day sustained release from Qu-NP as compared to quercetin suspension, which indicated the reduced dosing frequency. Efficacy in diabetic rats suggested that same dose of Qu-NP on every fifth day was sufficient to bring effect similar to daily dose of oral quercetin suspension, and the same effect was also observed for catalase and superoxide dismutase levels in pancreas and kidneys. Thus, the system offers an efficacious oral therapy with reduced dose and dosing frequency for treatment of diabetes and is hence patient compliant.