BACKGROUND: Myeloma-related bone disease (MBD) is a common complication of multiple myeloma (MM) that deteriorates patients' quality of life and affects overall survival. Modulating the interaction between myeloma cells and the bone marrow microenvironment may offer therapeutic potential. While certain natural medicines may regulate bone homeostasis by directly targeting osteoclasts or osteoblasts, few studies have explored the effects of intervening in myeloma cells on osteoclasts, particularly through the role of exosomes. PURPOSE: To investigate the inhibitory effect of Guizhi Fuling Decoction (GZFL) on bone lesions formation induced by exosomes secreted by myeloma cells and provide evidence to support the clinical application of GZFL in treating MBD. METHODS: TRAP staining and Von Kossa staining were used to evaluate the inhibition of GZFL on RANKL-induced osteoclastogenesis in vitro. Micro-CT and bone histomorphometric analyses were performed to identify the protective effect of GZFL on bone destruction in vivo. RNA immunoprecipitation (RIP), RNA-seq, and UHPLC-MS/MS were conducted to investigate the MBD targets of GZFL. A clinical trial was carried out to evaluate the efficacy of GZFL capsules in the treatment of MBD. RESULTS: The main bioactive components of GZFL, paeoniflorin, quercitrin and kaempferol, could target ERK1 and downregulate its expression in MM exosomes. In vitro, GZFL treatment inhibited the promoting effect of MM exosomes on osteoclast (OC) formation, bone resorption, and activated ERK1 expression. In vivo, GZFL prolonged survival rate, inhibited the exacerbation of bone lesions caused by MM exosomes and RANKL-induced ERK1 activation in mice model. Clinical data showed that GZFL capsule combined with bortezomib (Bortezomib) and dexamethasone (PD) significantly reduced the numeric rating scale, as well as the expression levels of ERK and RANKL in bone marrow. ERK1 levels exhibited a positive correlation with both the number of bone lesions and RANKL levels. Higher ERK1 expression indicated a worse prognosis. CONCLUSION: GZFL inhibited MBD progression by reducing MM-derived exosomal ERK1, thereby suppressing RANKL-induced ERK1 activation and the downstream OC formation. GZFL combined with PD regimen had good clinical efficacy and safety in the treatment of MBD.