With the continuing demographic shift in population toward an older society, all industrialised countries face a growing prevalence of chronic age-related conditions. Among those diseases, impaired capacities of movement due to osteoporosis, are especially disabling. Indeed, osteoporosis is a major public health problem characterized by a reduced bone mass and disruption of bone architecture, resulting in increased bone fragility. While the social and economic burden of the disease is growing at an alarming rate, health professionals deplore the lack of prophylactic tools and the fact that only 10% of women with fragility fractures receive any osteoporosis therapy due to several side effects. Moreover, the poor access to treatments is compounded by poor adherence. This is why the authorities and the public health systems strongly advocate implementing new strategies of proven scientific value. A growing body of evidence has contributed to stress the importance of nutritional preventive measures for bone health. However, so far, research has been limited to calcium and vitamin D. The putative interest of polyphenols offers a new concept based on their antioxidant and anti-inflammatory properties, but also their ability to modulate various signaling pathways. Among those compounds, fisetin has been shown to positively modulate bone physiology and to prevent estrogen deficiency and inflammation-induced osteoporosis. This very potent compound exhibits a dual role by promoting osteoblast and repressing osteoclast differentiation processes, both in vivo and in vitro. The complete mechanism of action was deciphered, starting from physiological-based evidences in experimental models to reach the most detailed mediating molecular pathways in bone cells.