Two dimensional nanoparticles (2D‐NPs) along with other nanoscale materials have been deemed to be the next generation of artificial enzymes (nanozymes). The low‐cost bulk‐scale production, ease of storage and modification of such nanomaterials have given nanozymes an advantage over traditional enzymes. Many studies have been aimed at developing methods to increase the performance of these nanozymes, and also identify interfering agents. To investigate the interference of a number of metal cations, we studied the effect of Ti2+, Fe2+, Ag+, Hg2+, Co2+, Cu2+, Ni2+, Pb2+, Ca2+, Zn2+ and Mn2+ in a nanozyme assays of 2D‐NPs using ABTS radical formation. Ti2+, Co2+, Cu2+, Ni2+, Ca2+, Zn2+ and Mn2+ ions did not display any notable effect on the peroxidase‐like activity of nGO, MoS2 and WS2 2D‐NPs. However, Fe2+, Ag+, Hg2+ and Pb2+ ions’ effects on the overall ABTS reaction were significant enough to be visualised by partial least square discriminant analysis (PLSDA). We report that, similar to that of many natural enzymes, the nanozyme activity of 2D‐NPs is regulated by a number of metal cations allowing their identification and discrimination by using a statistical analysis tool.