This study aimed to develop nanoliposomal crocin formulations for the treatment of rheumatoid arthritis. Three crocin-loaded formulations including hydrogenated soy phosphatidylcholine (HSPC), 1,2- distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DSPG) and cholesterol (Chol) were made at different molar ratios using a solvent evaporation method plus extrusion. Two formulations contained methoxy-polyethylene glycol (MW 2000)-distearoylphosphatidylethanolamine. Based on the characterization tests, the crocin encapsulation efficiency of the formulations was between 85.3% and 95.6%, and the crocin release of the formulations was less than 40%, with the stability of about 12 weeks at 4 °C storage. To evaluate the anti-arthritic activity of nanoliposomal formulations, an adjuvant-induced arthritis (AIA) model was used. Rats were randomly divided into six groups. Changes in paw edema, biochemical parameters, and histopathology were then evaluated. The results showed that F1 nanoliposomes reduced serum levels of TNFα, IL1β, and IL17 cytokines, biochemical parameters (ALP, ALT, and AST), and paw edema in comparison to the AIA rats in the control groups. In conclusion, crocin-loaded liposomes can serve as a favorable agent in enhancing the anti-arthritic efficacy of crocin by decreasing the symptoms and controlling proinflammatory molecules.