Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, epigenetically regulates various cell metabolisms, including inflammation, tumorigenesis, and bone metabolism. Many clinical studies have found the potential of SIRT1 in predicting and treating bone-related disorders, such as osteoporosis and osteonecrosis, suggesting that SIRT1 might be a regulator of bone homeostasis. In order to identify the mechanisms that underlie the pivotal role of SIRT1 in bone homeostasis, many studies revealed that SIRT1 could maintain the balance between bone formation and absorption via regulating the ratio of osteoblasts to osteoclasts. SIRT1 controls the differentiation of mesenchymal stem cells (MSCs) and bone marrow-derived macrophages, increasing osteogenesis and reducing osteoclastogenesis. Besides, SIRT1 can enhance bone-forming cells' viability, including MSCs and osteoblasts under adverse conditions by resisting senescence, suppressing apoptosis, and promoting autophagy in favor of osteogenesis. Furthermore, the effect on bone vasculature homeostasis enables SIRT1 to become a valuable strategy for ischemic osteonecrosis and senile osteoporosis. The review systemically discusses SIRT1 pathways and the critical role in bone homeostasis and assesses whether SIRT1 is a potential target for manipulation and therapy, to lay a solid foundation for further researches in the future.