Metabolic inflammation, a low-grade chronic pro-inflammatory environment in metabolic or vascular tissues during nutrient excess, has emerged as an important factor underpinning the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Macrophages are a primary source of inflammatory effectors that contribute to insulin resistance and atherosclerosis, the precursors of T2D and CVD, respectively. Oxidative metabolism dictates the inflammatory status of macrophages, effects that may be upstream of endoplasmic reticulum (ER) stress and the NLRP3 inflammasome. The AMP-activated protein kinase (AMPK) lies at the crossroads of metabolically driven macrophage inflammation and exerts control over mitochondrial metabolism, and therefore is vital for dictating the inflammatory status of macrophages. Understanding how AMPK regulates oxidative metabolism and substrate selection to control both ER stress and NLRP3 inflammasome-mediated inflammation holds promise for identifying new therapies and the tailoring of current therapies for the treatment of T2D and CVD.