Osteolytic bone lesions are one of the central features of multiple myeloma (MM) and lead to bone pain, fractures, decreased quality of life, and decreased survival. Dysfunction of the osteoclast (OC)/osteoblast (OB) axis plays a key role in the development of myeloma-associated osteolytic lesions. Many signaling pathways and factors are associated with myeloma bone diseases (MBDs), including the RANKL/OPG and NF-κB pathways. NRF2, a master regulator of inflammatory signaling, might play a role in the regulation of bone metabolism via anti-inflammatory signaling and decreased reactive oxygen species (ROS) levels. The loss of NRF2 expression in OCs reduced bone mass via the RANK/RANKL pathway and other downstream signaling pathways that affect osteoclastogenesis. The NRF2 level in OBs could interfere with interleukin (IL)-6 expression, which is associated with bone metabolism and myeloma cells. In addition to direct impact on OCs and OBs, the activity of NRF2 on myeloma cells and mesenchymal stromal cells influences the inflammatory stress/ROS level in these cells, which has an impact on OCs, OBs, and osteocytes. The interaction between these cells and OCs affects the osteoclastogenesis of myeloma bone lesions associated with NRF2. Therefore, we have reviewed the effects of NRF2 on OCs and OBs in MBDs.