Abstractβ‐Lactam antibiotics are one of the most commonly prescribed drugs to treat bacterial infections. However, their use has been somehow limited given the emergence of bacteria with resistance mechanisms, such as β‐lactamases, which inactivate them by degrading their four‐membered β‐lactam rings. So, a total knowledge of the mechanisms governing the catalytic activity of β‐lactamases is required. Here, we report a novel Zn‐based metal–organic framework (MOF, 1), possessing functional channels capable to accommodate and interact with antibiotics, which catalyze the selective hydrolysis of the penicillinic antibiotics amoxicillin and ceftriaxone. In particular, MOF 1 degrades, very efficiently, the four‐membered β‐lactam ring of amoxicillin, acting as a β‐lactamase mimic, and expands the very limited number of MOFs capable to mimic catalytic enzymatic processes. Combined single‐crystal X‐ray diffraction (SCXRD) studies and density functional (DFT) calculations offer unique snapshots on the host‐guest interactions established between amoxicillin and the functional channels of 1. This allows to propose a degradation mechanism based on the activation of a water molecule, promoted by a Zn‐bridging hydroxyl group, concertedly to the nucleophilic attack to the carbonyl moiety and the cleaving of C−N bond of the lactam ring.