Mimicking enzyme specificity via construction of on-demand geometric structures on nanozymes is of great interest in recent years. Although building substrate-specific polymers on nanozymes has achieved great success, polymer-blocked active sites would inevitably lead to decreased activity of nanozymes. Here, we have developed three photoactive metal-organic framework (MOF)-based nanozymes (called 2D-TCPP, 3D-TCPP, and AD-TCPP), which have different geometric structures as well as unshielded active sites. Together with their structural variations and excellent photoresponsive oxidase-like activities, these photoactive nanozymes exhibit structure-dependent specificity for three kinds of substrates (typical oxidase substrates, organic pollutants, and antioxidants). Moreover, AD-TCPP and 3D-TCPP show potential applications for environmental protection and bioanalysis, respectively. This work offers a promising approach to the development of nanozymes with enzyme-like specificity.