Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a role in cell differentiation, proliferation, apoptosis, redox balance, amino acid uptake, and glycolipid metabolism. ATF4 induces the differentiation of bone marrow mesenchymal stem cells (BM-MSCs) into osteoblasts, increases osteoblast activity, and inhibits osteoclast formation, promoting bone formation and remodeling. In addition, ATF4 mediates the energy metabolism in osteoblasts and promotes angiogenesis. ATF4 is also involved in the mediation of adipogenesis. ATF4 can selectively accumulate in osteoblasts. ATF4 can directly interact with RUNT-related transcription factor 2 (RUNX2) and up-regulate the expression of osteocalcin (OCN) and osterix (Osx). Several upstream factors, such as Wnt/β-catenin and BMP2/Smad signaling pathways, have been involved in ATF4-mediated osteoblast differentiation. ATF4 promotes osteoclastogenesis by mediating the receptor activator of nuclear factor κ-B (NF-κB) ligand (RANKL) signaling. Several agents, such as parathyroid (PTH), melatonin, and natural compounds, have been reported to regulate ATF4 expression and mediate bone metabolism. In this review, we comprehensively discuss the biological activities of ATF4 in maintaining bone homeostasis and inhibiting OP development. ATF4 has become a therapeutic target for OP treatment.