Direct conversion of methane to high value‐added oxygenates under mild conditions has attracted extensive interest. However, the over‐oxidation of target products is usually unavoidable due to the easily excessive activation of C−H bond on the sites of supported metal species. Here, we identified the most efficient Zr‐oxo nodes of UiO‐66 metal‐organic frameworks (MOFs) catalysts for the selective oxidation of methane with H2O2. These nodes were modified by three types of benzene 1, 4‐dicarboxylates (NH2‐BDC, H2BDC, and NO2‐BDC). Detailed characterizations and DFT calculations revealed that these ligands can effectively tune the electronic properties of Zr‐oxo nodes and the H2BDC ligand led to optimal electronic density of Zr‐oxo nodes in UiO‐66. Thus the UiO‐66‐H catalyst promoted the formation of ⋅OH species that adsorbed on Zr‐oxo nodes, and facilitated the activation of methane with a lower energy barrier and subsequent conversion to hydroxylation oxygenates with 100 % selectivity. [ABSTRACT FROM AUTHOR]