Systemic rheumatoid arthritis (RA) regimens fail to attain effective drug level at the affected joints and are associated with serious side effects. Herein, an attempt made to improve therapeutic outcomes of both leflunomide (LEF) which is a disease modifying antirheumatic and dexamethasone (Dex) through local delivery of combination therapy by intra-articular route. LEF and Dex were encapsulated in nanostructured lipid carriers (NLCs) and PLGA nanoparticles (NPs), respectively. Both nanocarriers were loaded into chitosan/β glycerophosphate (CS/βGP) thermo-sensitive hydrogels and injected intra-articularly in adjuvant induced RA rat model. Particle size of LEF NLCs and selected Dex NPs formulations were 200 and 119 nm, respectively. Dex NPs and LEF NLCs showed a sustained release profile for up to 58 and 17 days, respectively. After 14 days of treatment remarkable joint healing was observed for groups treated with Dex NPs in combination with either free LEF or LEF NLCs in CS/βGP hydrogel. Joint diameter measurements, TNF α levels and histopathological examination of dissected joints showed comparable values to the negative control group. This might be attributed to the synergistic effect of drug combination besides the ability of nanocarriers loaded hydrogel to prolong joint residence time and enhance joint healing potential.Copyright © 2021. Published by Elsevier Inc.