Oxidative stress and inflammation are central pathophysiological processes in a traumatic spinal cord injury (SCI). Antioxidant therapies that reduce the reactive oxygen and nitrogen species (RONS) overgeneration and inflammation are proved promising for improving the outcomes. However, efficient and long-lasting antioxidant therapy to eliminate multiple RONS with effective neuroprotection remains challenging. Here, a single-atom cobalt nanozyme (Co-SAzyme) with a hollow structure was reported to reduce the RONS and inflammation in the secondary injury of SCI. Among SAzymes featuring different single metal-N sites (e.g., Mn, Fe, Co, Ni, and Cu), this Co-SAzyme showed a versatile property to eliminate hydrogen peroxide (H₂O₂), superoxide anion (O₂^•−), hydroxyl radical (·OH), nitric oxide (·NO), and peroxynitrite (ONOO⁻) that overexpressed in the early stage of SCI. The porous hollow structure also allowed the encapsulation and sustained release of minocycline for neuroprotection in synergy. In vitro results showed that the Co-SAzyme reduced the apoptosis and pro-inflammatory cytokine levels of microglial cells under oxidative stress. In addition, the Co-SAzyme combined with minocycline achieved remarkable improved functional recovery and neural repairs in the SCI-rat model.