In humans, irisin is produced mainly by skeletal muscle in response to physical activity. It has been demonstrated that irisin plays a pivotal role in inducing fat browning and regulating energy expenditure. New findings from various studies conducted in both animals and humans suggest that irisin can affect bone and glucose metabolism. In particular, irisin is able to increase bone cortical mass by stimulating the osteoblast pathways, and irisin levels are inversely correlated with the incidence of fragility fractures among postmenopausal women affected by osteoporosis. Most available evidence shows that irisin significantly influences glucose and energy homeostasis. Indeed, higher irisin concentrations are inversely correlated with type 2 diabetes. Unfortunately, contradictory findings exist concerning the role of irisin in humans, and most of the human studies that have analyzed interactions between bone health, glucose metabolism, and irisin have several limitations; therefore, their results must be interpreted with caution. The purpose of this narrative review is mainly to describe the effects of irisin on glucose and bone metabolism.