Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223-regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.