The reaction of nitric oxide (NO) on Cu(100) is studied by scanning tunneling microscopy, electron energy loss spectroscopy and density functional theory calculations. The NO molecules adsorb mainly as monomers at 64 K, and react and dissociate to yield oxygen atoms on the surface at ∼70 K. The temperature required for the dissociation is significantly low for Cu(100), compared to those for Cu(111) and Cu(110). The minimum energy pathway of the reaction is via (NO)₂ formation, which converts into a flat-lying ONNO and then dissociates into N₂O and O with a considerably low activation energy. We propose that the formation of (NO)₂ and flat-lying ONNO is the key to the exceptionally high reactivity of NO on Cu(100).