The separation of hexane isomers into their individual components, especially the mono- and di-branched isomers, is one of the most important while challenging industrial processes for the production of high-octane gasoline. In this work, a pore-engineered metal-organic framework with mixed ligands, CAU-10-H/Br, is designed based on the parent structures of CAU-10-H and CAU-10-Br through multivariate metal-organic frameworks strategy, whose channels partially decorated with -Br group possess suitable pore size (5.4 Å), enabling access to n-hexane (4.3 Å) and 3-methylpentane (5.0 Å), but excluding 2,2-dimethylbutane (6.2 Å). The adsorption isotherms indicate that this material has adequate adsorption capacity of n-hexane and 3-methylpentane, about 1.5 and 0.7 mmol⋅g−1 at 303 K and the pressure of 50 Torr, respectively. CAU-10-H/Br shows extraordinary separation performance exceeding most of the reported MOFs in the breakthrough experiments, manifested as almost complete exclusion of 2,2-dimethylbutane and sufficient separation time between 3-methylpentane and 2,2-dimethylbutane. The configurational-bias Monte Carlo and density functional theory calculations reveal the orientations of the guest molecules in the channels and the adsorption sites for host-guest interaction. Moreover, the high stability of CAU-10-H/Br suggests it has a huge potential in the industrial separation of hexane isomers.