The high computility of electronic components put urgent requirements on the dissipation efficiency of a high thermal conductive substrate. Herein, inspired by the nature structure, leaf-vein-like Al2O3 skeleton was first designed though topology optimization algorithm and manufactured via vat photopolymerization (VPP) 3D printing, then compounded with epoxy (EP) to prepare leaf-vein-like biohybrid structures. The biohybrid structure had a high λ (14.65 Wm–1 K–1 with the solid fraction of 40 vol %), which was 5585% higher than neat EP and 269% higher than the random dispersed Al2O3/EP composite at the same solid amount. Moreover, it further showed a high enhancement in the cooling ecoefficiency of the lighting-emitting diode (LED) cooling system. Compared with 40 vol % random dispersed Al2O3/EP composite as a cooling substrate, the leaf-vein-like biohybrid structure with the same solid fraction reduced the working temperature of LED by 8.9 °C. Our strategy has a significant potential as a viable type and mass-producible bionic cooling substrate.