Our previous studies have confirmed that resveratrol (RSV) can prevent the development of osteoarthritis through a variety of mechanisms, such as apoptosis inhibition, autophagy induction and SIRT 1 activation. However, the pharmaceutical application of RSV is mainly limited by its low bioavailability. Here, we designed and synthesized RSV-loaded poly (D, l-lactide-coglycolide acid) (PLGA)-nanoparticles (NPs). The average particle size, polydispersity index and positive charge of RSV-loaded PLGA NPs were 50.40 nm, 0.217 and 12.57 mV, respectively. These nanoparticles had marked encapsulation efficiency (92.35 %) and drug loading (15.1 %) for RSV. It was found that RSV-loaded PLGA NPs not only inhibited the apoptosis of chondrocytes induced by IL-1, but also rescued GAG loss in vitro. Pharmacokinetic data showed that RSV-loaded PLGA NPs demonstrated a significantly profound and prolonged concentration profile in joint tissues, with quantifiable RSV concentrations over 35 days. The therapeutic effects of RSV-loaded PLGA NPs were then examined in rat osteoarthritis models. In vitro magnetic resonance imaging results showed that RSV-loaded PLGA NPs treatment dramatically reduced both T1ρ and T2 relaxation times at 4, 8, 12 weeks during administration, implying that cartilage destruction was alleviated. Histological assessments showed that RSV-loaded PLGA NPs significantly improved osteoarthritis symptoms. Gene expression analysis revealed that osteoarthritis mediator genes were downregulated in rats treated with RSV-PLGA NPs. Mechanistic studies indicated that RSV-loaded PLGA NPs inhibit apoptosis and promote autophagy. Collectively, this study demonstrates that intra-articular delivery of RSV via PLGA NPs might be an effective therapeutic approach for osteoarthritis.