Obesity and osteoporosis are global health problems characterized by high rates of prevalence and mortality due to complications. As people with visceral obesity age, the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) increases, and adipocytes become the predominant stromal cells in the bone marrow microenvironment, which hinders the physiological regeneration and mineralization of bone tissue. Primary and secondary osteoporosis remain severe progressive diseases. Both osteoporosis and obesity are associated with microRNAs (miRNAs) that induce adipogenesis and osteoresorption. This review presents analyses of the roles and clinical potential of miRNAs in the epigenetic control of BMSC differentiation and the formation and function of osteoclasts in osteoporosis with and without obesity. Understanding the fine-tuned regulation of the expression of genes critical for the balance of osteogenesis/osteolysis processes may provide hope for the development of effective and safe osteoporosis therapies in the future.