The E2F family consists of transcription factors that mediate the induction of the E2 gene by adenovirus E1a and play a vital role in regulating cell cycle progression, cell proliferation, and cell apoptosis. Given its primary functions in cell proliferation and differentiation, early studies on the E2F family focused on its relationship with cancer. However, as research has expanded, the E2F family has been found to play an independent role in the development of the musculoskeletal system and the mechanisms of related diseases. The E2F family can influence the progression of musculoskeletal diseases by regulating the cell cycle and proliferation of stem cells, osteoblasts, osteoclasts, chondrocytes, and myoblasts, acting as a target gene for various downstream pathways and microRNAs. This review is divided into two parts: the first elaborates on the physiological roles of the E2F family in bone metabolism, skeletal muscle, and cartilage development, while the second summarizes its roles in the pathological processes of osteosarcoma, rheumatoid arthritis, osteoporosis, and muscle-related diseases. During musculoskeletal system development, the E2F family affects bone metabolism by regulating stem cell differentiation, promoting osteoclast differentiation and metabolism, and increasing osteoblast activity or inhibiting osteoblast differentiation. It also regulates mitosis in cartilage, influencing chondrocyte proliferation and differentiation. Additionally, the E2F family is essential for skeletal muscle development, controlling muscle differentiation and myogenesis. In the pathological mechanisms of musculoskeletal diseases, most E2F family members act as downstream targets of various microRNAs, regulating osteosarcoma progression. Some members function independently through their ability to control cell proliferation. The E2F family also contributes to osteoporosis progression by promoting pathological increases in osteoclast activity and affecting osteoblast function. In rheumatoid arthritis and osteoarthritis, E2F family members aggravate inflammation by increasing inflammatory factors through multiple pathways. Moreover, the E2F family plays a crucial role in muscle-related diseases, influencing skeletal muscle regeneration after injury and affecting symptoms of muscular dystrophies. This review provides a comprehensive overview of the physiological roles of the E2F family in the musculoskeletal system and its mechanisms of action in related diseases. By offering a systematic summary and analysis, this article aims to provide a foundation for future research as well as insights for disease diagnosis and treatment.