Abstract Metal–organic framework (MOF) membranes with tunable pore structure and chemical functionality are promising for molecular separation. Nevertheless, it remains a grand challenge to achieve precise molecular sieving and high flux simultaneously for liquid separation, especially for water desalination. Herein, for the first time, we report the design and engineering of hydrophobic Zr‐MOF, UiO‐66 membranes for membrane distillation. Thermal activation was proposed to remove the hydroxyl groups in the MOF framework to create a hydrophobic membrane surface, which ensures the membrane's anti‐wetting ability. Meanwhile, ligand concentration was regulated to introduce lattice defects to deliberately enlarge pore size, which facilitates the fast transport of water vapor. The relation between the hydroxyl groups and water transport was revealed by density functional theory calculations. The resulting hydrophobic MOF membrane showed excellent water desalination performance with a water flux of ~12.8 L·m −2 ·h −1 and NaCl rejection of over 99.9%. Our work extends the potential of MOF membrane for water desalination and also provides a facile approach to tuning the pore properties of molecular sieving membranes.