Monitoring l-cysteine (l-Cys) is of importance for human health and food safety. Herein, we designed a novel strategy for bimetallic Au and Ag/AgCl anchoring on Ni-doped ZIF-67 to form core-shell nanocubes (Ni-ZIF-67/AuAg/AgCl) using the galvanic replacement processes. The unique properties of ZIF-67 nanocubes were conducive to generating strong synergistic catalytic effects with Au and Ag/AgCl, particularly when Ni-ZIF-67/AuAg/AgCl composites were employed as oxidase mimics for catalyzing the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). The Ni-ZIF-67/AuAg/AgCl composites displayed strong affinity toward TMB, displaying a lower Michaelis constant Km value of 0.25 mM and a higher maximum initial rate Vmax of 9 × 10-8 M s-1. By virtue of the nanozyme, the colorimetric sensor was constructed for l-Cys detection with a relatively low detection limit of 0.051 μM. The superior catalytic performance of the as-prepared Ni-ZIF-67/AuAg/AgCl composites can be ascribed to the core-shell structure, large specific surface area, and strong synergistic catalytic effects, which are beneficial for exposing more active sites and enhancing the conductivity to further boost their catalytic activity.