Metal-organic frameworks (MOFs) provide an ideal platform for precise regulation of hydrophilicity and hydrophobicity, owing to their highly customizable pore architectures and tunable surface chemistry. This review systematically summarizes two primary strategies for modulating MOFs wettability: the direct incorporation of functionalized ligands during synthesis, and post-synthetic modification through grafting of specific functional groups or application of functional coatings. These approaches have enabled the construction of MOF-based materials with tunable wettability spanning from hydrophilic to hydrophobic. In separation science, MOFs with tailored surface properties demonstrate exceptional performance in oil-water separation, liquid purification under humid conditions, and efficient enrichment of biomolecules via selective adsorption and molecular sieving mechanisms. Furthermore, in catalysis, the creation of well-defined hydrophilic/hydrophobic microenvironments within MOFs enhances catalytic performance by promoting reactant enrichment and inhibitor exclusion, leading to significantly improved efficiency and selectivity in many catalytic reactions.