Osteoarthritis (OA) is one of the most frequent degenerative joint disease characterized by joint pain and stiffness traditionally treated with symptomatic drugs like oral NSAIDs and, in extreme cases, with intra-articular corticoids. However, both these drugs are not exempt from adverse effects. Curcumin (Cur) has proven its anti-inflammatory properties and its potential as anti-osteoarthritic drug. However, its low solubility hinders its usage and limits its therapeutic efficacy. To overcome this issue, drug-in-cyclodextrin double-loaded liposomes (DCL-DL) were developed. These liposomes contained free drug in the lipid bilayer and drug-cyclodextrin complex in the aqueous compartment. The aim of this work was to evaluate the actual effectiveness of Cur-DCL-DL formulations in the OA treatment by intra-articular treatment. For this purpose, the monoiodoacetate (MIA) model of OA pain in rats was used. A single dose of samples containing Cur as DCL-DL, conventional liposomes (SL) and empty liposomes (EL, as control) were injected once intra-articularly. Paw-pressure, beam-balance and incapacitation tests were performed to evaluate OA progression at 7 and 14 days. After ending the assay, animals were sacrificed, and histological evaluation of the ankle-joint tissue was performed. Results showed that DCL-DL significantly reduced pain and ameliorated balance and gait of rats over the 14 days compared to SL. Histological tests showed that DCL-DL had protective properties in some aspects of OA.