Discharge of recalcitrant pharmaceuticals into aquatic systems has caused severe impacts on public health and ecosystem. Advanced oxidation processes (AOPs) are effective for eliminating these refractory pollutants, for which single-atom catalysts (SACs) become the state-of-the-art materials owing to the maximized exposure of active metal sites. In this work, hollow spherical graphitic carbon nitride (hsCN) was fabricated to incorporate copper species to develop Fenton-like catalysts for acetaminophen (ACT) removal. Through pyrolysis of supramolecular assemblies derived from melamine-Cu complex and cyanuric acid, single atom Cu-N3 sites were anchored on hsCN by N-coordination to obtain SACu-hsCN. In virtue of the atomically dispersed Cu-N3 sites as well as the hollow structure of hsCN providing smooth channels for the interactions between single Cu atoms and reactants, the optimal 5.5SACu-hsCN removed 94.8% of ACT after 180 min of Fenton-like reactions, which was superior to that of 5.5AGCu-hsCN with aggregated Cu particles on hsCN (56.7% in 180 min). Moreover, 5.5SACu-hsCN was still active after four cycles of regeneration. The mechanism investigation demonstrated that both hydroxyl radicals ([rad]OH) and singlet oxygen (1O2) contributed to ACT degradation in 5.5SACu-hsCN/H2O2 system, in which non-radical 1O2 played the dominant role.