Cerium dioxide (CeO₂) nanocatalysts were initially grown in situ on 2D graphitic carbon nitride (g-C₃N₄) nanosheets to yield the nanocomposites g-C₃N₄/CeO₂ with a spherical structure for the catalysis-based colorimetric analysis of Hg²⁺ ions in blood and wastewater. As the synergetic introduction of g-C₃N₄ nanosheets might promote the electron transfer in CeO₂, the resulting g-C₃N₄/CeO₂ nanozyme was found to present greatly enhanced catalytic activity, as demonstrated by the steady-state kinetic studies, which is nearly 4-fold higher than that of pure CeO₂. Moreover, the g-C₃N₄/CeO₂ nanozymes would aggregate in the presence of Hg²⁺ ions due to the strong interaction between Hg²⁺ and the nitrogen of g-C₃N₄, leading to a decrease of catalysis rationally depending on the Hg²⁺ ion concentration. A colorimetric analysis strategy is therefore developed for the selective detection of Hg²⁺ ions separately in the complex samples of blood and wastewater, showing a linear concentration range from 0.50 nM to 800 nM with the LOD of 0.23 nM as exemplified for Hg²⁺ ions in blood. Also, the recovery tests indicated that the developed colorimetric method can allow for the accurate analysis of Hg²⁺ ions in wastewater and blood. Such a route for the fabrication of composite nanozymes by growing catalytic nanomaterials on conductive 2D substrates may be extended to the design of other kinds of nanozymes with enhanced catalytic performances for developing catalysis-based detection platforms.