Hydrogen peroxide (H₂O₂) in situ electrosynthesis by O₂ reduction reaction is a promising alternative to the conventional Fenton treatment of refractory wastewater. However, O₂ mass transfer limitation, cathodic catalyst selectivity, and electron transfer in O₂ reduction remain major engineering obstacles. Here, we have proposed a systematic solution for efficient H₂O₂ generation and its electro-Fenton (EF) application for refractory organic degradation based on the fabrication of a novel ZrO₂/CMK-3/PTFE cathode, in which polytetrafluoroethylene (PTFE) acted as a hydrophobic modifier to strengthen the O₂ mass transfer, ZrO₂ was adopted as a hydrophilic modifier to enhance the electron transfer of O₂ reduction, and mesoporous carbon (CMK-3) was utilized as a catalyst substrate to provide catalytic active sites. Moreover, feasible mass transfer of O₂ from the hydrophobic to the hydrophilic layer was designed to increase the contact between O₂ and the reaction interface. The H₂O₂ yield of the ZrO₂/CMK-3/PTFE cathode was significantly improved by approximately 7.56 times compared to that of the conventional gas diffusion cathode under the same conditions. The H₂O₂ generation rate and Faraday efficiency reached 125.98 mg·cm⁻²·h⁻¹ (normalized to 5674.04 mmol·g⁻¹·h⁻¹ by catalyst loading) and 78.24% at −1.3 V versus standard hydrogen electrode (current density of −252 mA·cm⁻²), respectively. The high H₂O₂ yield ensured that sufficient ·OH was produced for excellent EF performance, resulting in a degradation efficiency of over 96% for refractory organics. This study offers a novel engineering solution for the efficient treatment of refractory wastewater using EF technology based on in situ high-yield H₂O₂ electrosynthesis.