This paper focuses on the fabrication of electrochemical sensor based on core–shell heterostructure of NiCo–OH@C–ZnSe–CoSe2/Zn–Co-ZIF to efficient recognition of guanine. First, the bimetallic Zn/Co-ZIF precursor was obtained via facile solvothermal method and then coated with uniform PDA layer. Finally, the target material named PDA@Zn/Co-ZIF was synthesized by selenization and calcination processes at inert atmosphere and used as a core. The combination of reconstructed ZIFs as a core and transition metal layered double hydroxides (LDHs) as a shell led to the construction of a new catalyst with a core-shell structure and unique properties such as more exposed electrochemical active sites and high conductivity due to the strong synergistic effects between core and shell. The guanine based amperometric sensor was shown two linear responses in the range of 0.1 μM–2 μM and 2 μM–56 μM with a detection limit of 0.03 μM (S/N = 3). In addition, the proposed sensor exhibited satisfactory reproducibility with relative standard deviation (RSD) of 1%, excellent anti-interference ability, and favorable stability.