Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease. Display omitted •Mouse and human M1 macrophages fail to repolarize to M2 upon IL-4 restimulation•LPS + IFNγ treatment inhibits mitochondrial oxidative respiration in macrophages•Mitochondrial function is required for the repolarization to an M2 phenotype•NO blunts mitochondrial respiration and prevents plasticity in M1 macrophages Editing macrophage polarization is an emerging concept for the treatment of inflammatory diseases. Van den Bossche et al. show that inflammatory M1 macrophage activation dampens mitochondrial function, thereby preventing the repolarization to an anti-inflammatory M2 phenotype. Inhibiting nitric oxide production improves mitochondrial function and reprogramming to M2 macrophages.