The oral controlled release (CR) formulations have become more important in recent years. Among them, the polymeric nanoparticles have been thoroughly studied during the last decades, consequently they are extensively employed for a broad range of applications and drugs. The objective of this research was to develop polymeric nanoparticles (NPs) of ibuprofen with poly(lactic-co-glycolic) acid (PLGA) as polymer, and to test their applicability for oral CR formulations development. Different proportions of drug/polymer were employed to develop the ibuprofen NPs and their in vitro release profiles were analysed. The in situ segmental permeability of ibuprofen was tested in Wistar rat and demonstrated the high permeability of ibuprofen in rat colon. In addition, in vivo assays were performed to study the plasma concentration-time profiles of encapsulated versus non-encapsulated ibuprofen. The results showed that ibuprofen release from the NPs was pH-dependent and consequently higher at colonic pH. Moreover, the plasma concentration-time profiles reveal a controlled release from the ibuprofen NP. Therefore, the ibuprofen PLGA-NPs will be a good CR formulation to achieve a controlled release targeted to the colon, where the release rate of the drug from the NPs will be the limiting factor for the absorption process.