Rheumatoid arthritis (RA) is an autoimmune disease that seriously threatens human health and affects the quality of life of patients. At present, pharmacotherapy is still the mainstream treatment for RA, but most methods have shortcomings, such as poor drug targeting, a low effective drug dosage at the inflammatory site, and high systemic toxicity. The combined application of drug-loaded nanobubbles and ultrasound technology provides a new technique for the treatment of RA. Low-intensity focused ultrasound (LIFU) traces the transmission of drug-loaded nanobubbles in the body, and high-intensity focused ultrasound (HIFU) causes the nanobubbles to rupture to release drugs at the inflammatory site, thereby reducing their toxicity to normal tissues. In this study, a drug-loaded nanobubble delivery system (DEXsp@Liposomes/C3F8) with ultrasonic response characteristics was successfully constructed, and its therapeutic effect was evaluated for the treatment of RA in vitro and in vivo. DEXsp@Liposomes/C3F8 + LIFU had good biocompatibility and excellent ultrasound imaging ability. DEXsp@Liposomes/C3F8 +HIFU distinctly increased the cellular uptake of DEXsp and significantly reduced the secretion of related inflammatory factors in RAW264.7 cells. Moreover, DEXsp@Liposomes/C3F8 + HIFU effectively alleviated the symptoms of RA in model rats and significantly improved their exercise capacity. In conclusion, the prepared ultrasound-mediated DEXsp@Liposomes/C3F8 system exhibits good imaging, monitoring and therapeutic effects, and the results of this study provide a new direction for the diagnosis and treatment of RA.