The graphene-supported copper selenide (CuSe/rGO) nanohybrid was effectively synthesized using a one-pot hydrothermal method, which was subsequently evaluated for its enhanced peroxidase-like (POD-like) catalytic activity. CuSe nanoparticles were homogeneously dispersed on the rGO nanosheets, resulting in enhanced interfacial interaction and improved electron transfer, as confirmed by structural and morphological analysis (FE-SEM and TEM). Compared to pristine CuSe, the CuSe/rGO nanohybrid exhibited superior catalytic efficiency in oxidizing color-changing substrates, such as o-phenylenediamine (OPD), with H2O2 as the oxidant. Mechanistic analysis revealed that the primary reactive species responsible for substrate oxidation were identified as hydroxyl radicals (•OH), whose formation is significantly enhanced by synergistic interactions and rapid electron transfer inside the nanohybrid. Overall, the CuSe/rGO nanohybrid exhibits remarkable properties as an economical and effective nanozyme for biomedical diagnostics, environmental monitoring, and biosensing applications.