Chronic overnutrition and obesity induces low-grade inflammation throughout the body. Termed “meta-inflammation,” this chronic state of inflammation is mediated by macrophages located within the colon, liver, muscle, and adipose tissue. A sentinel orchestrator of immune activity and homeostasis, macrophages adopt variable states of activation as a function of time and environmental cues. Meta-inflammation phenotypically skews these polarization states and has been linked to numerous metabolic disorders. The past decade has revealed several key regulators of macrophage polarization, including the signal transducer and activator of transcription family, the peroxisome proliferator–activated receptor gamma, the CCAAT–enhancer-binding proteins (C/EBP) family, and the interferon regulatory factors. Recent studies have also suggested that microRNAs and long noncoding RNA influence macrophage polarization. The pathogenic alteration of macrophage polarization in meta-inflammation is regulated by both extracellular and intracellular cues, resulting in distinct secretome profiles. Meta-inflammation-altered macrophage polarization has been linked to insulin insensitivity, atherosclerosis, inflammatory bowel disease, cancer, and autoimmunity. Thus, further mechanistic exploration into the skewing of macrophage polarization promises to have profound impacts on improving global health.