Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese herbal medicine Tripterygium wilfordii Hook F, offers immunosuppressive effects for RA treatment but is limited by poor solubility and bioavailability. In this study, long-circulating Cel-loaded liposomes (Cel-LPs) were used to increase the pharmacokinetics of Cel, thereby improving drug delivery and efficacy for the treatment of RA. Cel-LPs were prepared and administered orally and intravenously to compare the elimination half-life of drugs and bioavailability of Cel. Cel-LPs were prepared using the lipid thin-layer-hydration-extrusion method. Human rheumatoid arthritis synovial (MH7A) cells were used to investigate the compatibility of Cel-LPs. The pharmacokinetic studies were performed on male Sprague-Dawley (SD) rats. The Cel-LPs had an average size of 72.20 ± 27.99 nm, a PDI of 0.267, a zeta potential of -31.60 ± 6.81 mV, 78.77 ± 5.69% drug entrapment efficiency and sustained release (5.83 ± 0.42% drug loading). The cytotoxicity test showed that liposomes had excellent biocompatibility and the fluorescence microscope diagram indicated that liposome entrapment increased intracellular accumulation of Rhodamine B by MH7A cells. Furthermore, the results exhibited that Cel-LPs improved the pharmacokinetics of Cel by increasing the elimination half-life (t1/2) to 11.71 hr, mean residence time (MRT(0-∞)) to 7.98 hr and apparent volume of distribution (Vz/F) to 44.63 L/kg in rats, compared to the Cel solution. In this study, liposomes were demonstrated to be effective in optimizing the delivery of Cel, enabling the formulation of Cel-LPs with prolonged blood circulation and sustained release characteristics. This formulation enhanced the intravenous solubility and bioavailability of Cel, developing a foundation for its clinical application in RA and providing insights on poorly soluble drug management.