Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting prodrugs into drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization. The existing MEMs can be classified into three categories: catalytic core-scaffold MEM (csMEM), nanoparticle MEM (npMEMs) and metal-organic framework (MOF) MEM (mofMEM). These MEMs can mimic diverse functions corresponding to natural enzymes, and some of which are potentially used in prodrug activation, such as DNase, RNase, carbonate esterase, etc. In this review, we briefly summarize the MEMs according to their structure and composition, and highlight the successful and potential applications for prodrug activation mediated by hydrolase-like and oxidoreductase-like MEMs.