Abstract The improvement of the Total Isomerization Process (TIP) for the production of high‐quality gasoline with the ultimate goal of reaching a Research Octane Number (RON) higher than 92 requires the use of specific sorbents to separate pentane and hexane isomers into classes of linear, mono‐ and di‐branched isomers. Herein we report the design of a new multi‐cage microporous Fe(III)‐MOF (referred to as MIP‐214, MIP stands for materials of the Institute of Porous Materials of Paris) with a flu‐e topology, incorporating an asymmetric heterofunctional ditopic ligand, 4‐pyrazolecarboxylic acid, that exhibits an appropriate microporous structure for a thermodynamic‐controlled separation of hydrocarbon isomers. This MOF produced via a direct, scalable, and mild synthesis route was proven to encompass a unique separation of C5/C6 isomers by classes of low RON over high RON alkanes with a sorption hierarchy: (n‐hexane≫n‐pentane≈2‐methylpentane>3‐methylpentane) low RON ≫(2,3‐dimethylbutane≈i‐pentane≈2,2‐dimethylbutane) high RON following the adsorption enthalpy sequence. We reveal for the first time that a single sorbent can efficiently separate such a complex mixture of high RON di‐branched hexane and mono‐branched pentane isomers from their low RON counterparts, which is a major achievement reported so far.