Abstract Adiponectin is an abundantly secreted hormone that communicates information between the adipose tissue, and the immune and cardiovascular systems. In metabolically healthy individuals, adiponectin is usually found at high levels and helps improve insulin responsiveness of peripheral tissues, glucose tolerance, and fatty acid oxidation. Beyond its metabolic functions in insulin-sensitive tissues, adiponectin plays a prominent role in attenuating the development of atherosclerotic plaques, partially through regulating macrophage-mediated responses. In this context, adiponectin binds to its receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 on the cell surface of macrophages to activate a downstream signaling cascade and induce specific atheroprotective functions. Notably, macrophages modulate the stability of the plaque through their ability to switch between proinflammatory responders, and anti-inflammatory proresolving mediators. Traditionally, the extremes of the macrophage polarization spectrum span from M1 proinflammatory and M2 anti-inflammatory phenotypes. Previous evidence has demonstrated that the adiponectin-AdipoR pathway influences M1-M2 macrophage polarization; adiponectin promotes a shift toward an M2-like state, whereas AdipoR1- and AdipoR2-specific contributions are more nuanced. To explore these concepts in depth, we discuss in this review the effect of adiponectin and AdipoR1/R2 on 1) metabolic and immune responses, and 2) M1-M2 macrophage polarization, including their ability to attenuate atherosclerotic plaque inflammation, and their potential as therapeutic targets for clinical applications.