The peroxone reaction between O3 and H2O2 has been deemed a promising technology to resolve the increasingly serious water pollution problem by virtue of the generation of superactive hydroxyl radicals (•OH), but it suffers greatly from an extremely limited reaction rate constant under acidic conditions (ca. less than 0.1 M–1 s–1 at pH 3). This article describes a heterogeneous catalyst composed of single Mn atoms anchored on graphitic carbon nitride, which effectively overcomes such a drawback by altering the reaction pathway and thus dramatically promotes •OH generation in acid solution. Combined experimental and theoretical studies demonstrate Mn–N4 as the catalytically active sites. A distinctive catalytic pathway involving HO2• formation by the activation of H2O2 is found, which gets rid of the restriction of HO2– as the essential initiator in the conventional peroxone reaction. This work offers a new pathway of using a low-cost and easily accessible single-atom catalyst (SAC) and could inspire more catalytic oxidation strategies.