Disseminating antibiotic resistance rendered by bacteria against the widely used β-lactam antibiotics is a serious concern in the public health care. Development of inhibitors for drug-resistant β-lactamase enzymes is vital to combat this rapidly escalating problem. Recently, the Food and Drug Administration has approved a non-β-lactam inhibitor called avibactam for the treatment of complicated intra-abdominal and urinary tract infections caused by drug-resistant Gram-negative bacteria. This work sheds light on the molecular origin of the inhibitory effect of avibactam against drug resistant CTX-M variant of Class-A β-lactamase. Especially, we probed the structural evolution, dynamical features and energetics along the acylation and the deacylation reaction pathways through reliable enhanced sampling molecular dynamics methods and free energy calculations. We scrutinize the roles of active site residues, the nature of the carbonyl linkage formed in the inhibitor–enzyme covalent intermediate and other structural features of the inhibitor molecule. While unraveling the reasons behind the inhibition of all the deacylation routes, this study explains various experimental structural and kinetics data, and paves the way to design new inhibitors based on the β-lactam framework.