Separation of xylene isomers is one of the most important but most challenging and energy‐intensive separation processes in the petrochemical industry. Here, we report an adaptive hydrogen‐bonded organic framework (HOF‐29) constructed from a porphyrin based organic building block 4,4′,4′′,4′′′‐(porphyrin‐5,10,15,20‐tetrayl) tetrabenzonitrile (PTTBN), exhibiting the exclusive molecular recognition of p‐xylene (pX) over its isomers of o‐xylene (oX) and m‐xylene (mX), as clearly demonstrated in the single crystal structure transformation and 1H NMR studies. Single crystal structure studies show that single‐crystal‐to‐single‐crystal transformation from the as‐synthesized HOF‐29 to the pX exclusively included HOF‐29⊃pX is triggered by the encapsulation of pX molecules, accompanied by sliding of the 2D layers and local distortion of the ligand, which provides multiple C−H⋅⋅⋅π interactions.