Complexation copper with amine provides an effective strategy for fixation copper in wood, while hydrophobic modification improves the dimensional stability of wood. Thus, a combination of complexation and hydrophobization is expected to enhance the efficiency of copper-based biocides. In this study, hydrophobic hybrid silica gel containing copper amine complexes (MACu) was prepared through an in situ sol-gel process in wood using methyltriethoxysilane (MTES), 3-amino-propyltriethoxysilane (APTES), and copper chloride. The resistance to growth of molds for MACu modified wood (Populus tomentosa) was measured according to ASTM D3273-16. A leaching resistance test was carried out in accordance with AWPA E11-16. The results showed that only Aspergillus niger covered the surface of untreated wood blocks and no mold grew on the MACu surface even after the leaching test. MACu xerogel and MACu wood were further characterized by SEM-EDS, FTIR, and XPS. A possible schematic diagram of the reaction mechanism was proposed to explain the high-efficiency anti-mold performance of MACu wood.