High-energy–density lithium-sulfur batteries have been rated as a promising, yet challenging, next-generation battery technology. Typically, the serious shuttle of polysulfide intermediates and sluggish solid–solid reaction kinetics often result in irreversibly sulfur loss, low Coulombic efficiency, and limited lifespan. Herein, we propose a facile and efficient separator modification strategy using a rationally designed sulfiphilic and lithiophilic mediator, confinement growth of oxygen-deficient TiO nanoparticles within nitrogen-doped mesoporous carbon matrix to modulate the sulfur electrochemistry. The nanoscale defective catalyst within open mesoporous host affords favorable adsorption of polysulfides and catalytic conversion ability. Moreover, the versatile composite improves the electrolyte wettability and Li transfer kinetics and alleviates self-discharge behavior. Resultantly, the Li-S batteries using modified separator achieves significantly improved cycling stability with a low capacity decay of only 0.067% per cycle after 500 cycles at 2C. The defect engineering together with separator modification strategies enable efficient and durable Li-S batteries.