Bone defect is one of the urgent problems to be solved in clinics, and it is very important to construct efficient scaffold materials to facilitate bone tissue regeneration. Hydrogels, characterized by their unique three-dimensional network structure, serve as excellent biological scaffold materials. Their internal pores are capable of loading osteogenic drugs to expedite bone formation. The rate and quality of new bone formation are intimately linked with immune regulation and vascular remodeling. The strategic sequential release of drugs to balance inflammation and regulate vascular remodeling is crucial for initiating the osteogenic process. Through the design of hydrogel microstructures, it is possible to achieve sequential drug release and the drug action time can be prolonged, thereby catering to the multi-systemic collaborative regulation needs of osteosynthesis. The drug release rate within the hydrogel is governed by swelling control systems, physical control systems, chemical control systems, and environmental control systems. Utilizing these control systems to design hydrogel materials capable of multi-drug delivery optimizes the construction of the bone microenvironment. Consequently, this facilitates the spatiotemporal controlled released of drugs, promoting bone tissue regeneration. This paper reviews the principles of the controlled release system of various sustained-release hydrogels and the advancements in research on hydrogel multi-drug delivery systems for bone tissue regeneration. Display omitted •This paper explores a critical issue in the field of bone tissue regeneration, providing new insights and solutions.•This paper outlines the latest developments in hydrogel materials featuring multi-drug delivery capabilities.•This paper concludes the spatiotemporal controlled released hydrogels through analysis of bone regeneration procedures.