Abstract: The impact of weightlessness or simulated weightlessness on the cardiovascular system is a critical area of research in space medicine. Vascular smooth muscle cells (VSMCs) are the primary cellular components of the tunica media in blood vessels, maintaining vascular tension and function and play a vital role in the incidence and development of vascular diseases. In the microgravity environment of manned spaceflight, the absence of hydrostatic pressure in the body leads to distinct changes in vascular pressure across different parts of the human body, resulting in corresponding adaptive structural remodeling and functional alterations. The effects of weightlessness/simulated weightlessness significantly influence the proliferation, migration, apoptosis, and phenotypic transition of VSMCs, which are closely associated with the adaptive changes in vascular function and the development of various cardiovascular diseases. This review summarizes the effects and mechanisms of weightlessness/simulated weightlessness on VSMCs, providing valuable insights for understanding cardiovascular adaptations and preventing related conditions in astronauts following spaceflight.