Rheumatoid arthritis is a chronic systemic autoimmune disease that causes joint swelling and cartilage damage. The objective of the present work was to develop a temperature-sensitive hydrogel (D-NGel) containing nanoparticles (D-NPs), which could simultaneously deliver combination indomethacin and methotrexate. D-NPs were formed by multiple non-covalent interactions between PEI-SS and the carboxyl-containing hydrophobic small molecule drugs IND and MTX, which were then loaded into a temperature-sensitive hydrogel matrix. The T_sol/gel of the temperature-sensitive hydrogel matrix composed of 27% F127 and 10% F68 was 33 °C and the gelation time was less than 15 s. The resultant D-NGel was injected into the articular cavity of collagen-induced arthritis rats and quickly transformed in situ into gels which slowly released drug in the joint fluid for up to 72 h. The D-NGel effectively reduced joint swelling, bone erosion and expression of inflammatory cytokines in the ankle fluid and knee joint fluid. In addition, liver and kidney function tests and histopathological examination indicated there was a good biological safety for D-NGel. In conclusion, this work has demonstrated the great potential of the D-NGel for sustained co-delivery of IND and MTX for the synergistic treatment of rheumatoid arthritis, treating both the symptoms and the root causes of rheumatoid arthritis.