The advancements of quantum chemical methods and computer power allow detailed mechanistic investigations of metalloenzymes. In particular, both quantum chemical cluster and combined QM/MM approaches have been used, which have been proven to successfully complement experimental studies. This review starts with a brief introduction of nickel-dependent enzymes and then summarizes theoretical studies on the reaction mechanisms of these enzymes, including NiFe hydrogenase, methyl-coenzyme M reductase, nickel CO dehydrogenase, acetyl CoA synthase, acireductone dioxygenase, quercetin 2,4-dioxygenase, urease, lactate racemase, and superoxide dismutase.