Osteomyelitis is a severe bone condition caused by bacterial infection that can lead to lifelong disabilities or fatal sepsis. Given that the infection is stubborn and penetrates deep into the bone tissue, targeting and rapidly treating osteomyelitis remains a significant challenge. Herein, a triblock targeting peptide featuring ROS-cleavable linkage/antibacterial/bone-targeting unit was grafted onto the macrophage-derived exosomes (RAB-EXO). In vitro, effective eradication of osteomyelitis pathogens MRSA/E. coli and induction of M2 macrophage differentiation were triggered by RAB-EXO. In vivo, after intravenous administration of RAB-EXO, it can be targeted to bone tissue and release antimicrobial peptides in the high ROS environment of osteomyelitis. The released antimicrobial peptides markedly inhibit bacterial growth at infection sites. Moreover, M2 differentiation of bone tissue macrophages are facilitated by EXO, thereby decreasing the inflammatory factors and realizing the anti-inflammatory effect. Finally, a complete healing of osteomyelitis without adverse effects associated with traditional treatments is achieved within 28 days in rat models. Our findings confirm that RAB-EXO, as a targeted treatment for osteomyelitis, offers promising directions for addressing other bacterial infection diseases through similar mechanism such as periodontitis, rheumatoid arthritis.