Long-term administration of bisphosphonates can lead to a significant side effect known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although macrophage-mediated inflammation has been established as an important factor in BRONJ, the underlying mechanism remains elusive. In the current study, the roles of endoplasmic reticulum (ER) stress in zoledronic acid (ZOL)-induced inflammation were analyzed in macrophages, and the regulatory mechanism of ER stress activation was next investigated. An in vitro model of BRONJ was established by treating RAW264.7 cells with ZOL. The activation of ER stress was analyzed by western blotting and transmission electron microscopy, and inflammation was assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay. ER stress was significantly activated in ZOL-treated macrophages, and inhibition of ER stress by TUDCA, an ER stress inhibitor, suppressed ZOL-induced inflammation in macrophages. Mechanistically, phosphodiesterase 4B (PDE4B) was significantly increased in ZOL-treated macrophages. Forced expression of PDE4B promoted ER stress and inflammation, whereas PDE4B knockdown decreased ZOL-induced ER stress and inflammation in macrophages. More importantly, PDE4B inhibitor could improve ZOL-induced BRONJ in vivo. These data suggest that ZOL accelerates ER stress-mediated inflammation in BRONJ by increasing PDE4B expression. PDE4B inhibition may represent a potential therapeutic strategy for BRONJ. Subsequent research should concentrate on formulating medications that selectively target PDE4B, thereby mitigating the risk of BRONJ in patients undergoing bisphosphonate treatment.