Galectins are β-galactoside-binding proteins that bind and crosslink molecules via their sugar moieties, forming signaling and adhesion networks involved in cellular communication, differentiation, migration, and survival. Galectins are expressed ubiquitously across immune cells, and their function varies with their tissue-specific and subcellular location. Particularly galectin-1, -3, and -9 are highly expressed by inflammatory cells and are involved in the modulation of several innate and adaptive immune responses. Modulation in the expression of these proteins accompany major processes in cardiovascular diseases and metabolic disorders, such as atherosclerosis, thrombosis, obesity, and diabetes, making them attractive therapeutic targets. In this review we consider the broad cellular activities ascribed to galectin-1, -3, and -9, highlighting those linked to the progression of different inflammatory driven pathologies in the context of cardiovascular and metabolic disease, to better understand their mechanism of action and provide new insights into the design of novel therapeutic strategies.