With the development of space life science, researches on ground-based microgravity simulation become more and more important for spaceflight to complement their limited missions. It is well known that bone marrow mesenchymal stem cells (BMSCs) are pluripotent, self-renewing cells with multi-lineage differentiation capacity on the ground, but their responses under microgravity and the underlying regulatory mechanisms are poorly understood. Ground-based microgravity simulation might affect cell proliferation, apoptosis and expression of surface molecules, and induce cytoskeletal reorganization, as well as alter the differentiation potential of BMSCs. In this review, how groundbased microgravity simulation mediates BMSCs’ responses and its involved mechanisms are summarized to further understand the mechano-biological coupling in such process and provide theoretical references for space flight-induced pathophysiological alterations.