In this study, genipin cross-linked chitosan microspheres of flurbiprofen for intra-articular (i.a.) delivery were prepared. Emulsion-cross-linking method was used to prepare the microspheres using different concentrations of genipin and drug-to-polymer ratios. The mean particle size was found to be in the range of 5.18-9.74 μm with good % drug entrapment up to 80.97%. SEM indicated the spherical shape with smooth surface of drug-loaded cross-linked microspheres. FTIR confirmed cross-linking of genipin with chitosan and the absence of chemical interactions between drug, polymer, and cross-linker, which was further confirmed by TGA showing unaltered melting point of entrapped drug. DSC and XRD revealed the molecular dispersion of drug within microspheres. The optimized microspheres were able to release the drug for more than 108 h. The biocompatibility of the microspheres in the rat (Sprague-Dawley) knee joints was confirmed by histopathology. The results of pharmacokinetic study, decreased K(a) and T(max), lower C(max) and AUC((0-24)) and delayed MRT, suggested the significant extended release of flurbiprofen from microspheres in comparison with its solution at P<0.05. The recovery of flurbiprofen as the percent of administered dose followed by 24h after i.a. injection of microspheres was found to be 8.7 folds higher than its solution.