Silver (Ag) and gold (Au) nanoparticles (NPs) are incorporated into the zeolitic imidazolate framework-8 (ZIF-8) host matrix, which is successfully coated the screen-printed electrodes (SPEs) for the effective detection of chloramphenicol (CAP). The morphological and structural characteristics are examined using scanning electron microscope (SEM) and X-ray diffraction (XRD) analysis. Additionally, the electrochemical characteristics and sensing performance of CAP on the proposed electrodes are investigated in detail using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), chronoamperometry (CA), and differential pulse voltammetry (DPV) measurements, respectively. The results suggest the SPEs modified with Ag@ZIF-8 and Au@ZIF-8 exhibit impressive enhancements in sensitivity, linear concentration range, limits of detection (LODs), and repeatability. Under the optimum conditions, the proposed electrochemical sensors had a linear range of 0.25–50 μM for Ag@ZIF-8/SPE and 5–50 μM for Au@ZIF-8/SPE, corresponding to LODs of 0.16 and 0.404 μM, respectively. Notably, a series of kinetic parameters related to the redox reactions of both standard Fe(CN)6
3−/4− probe and CAP molecules in phosphate-buffered saline (PBS) buffer are determined. Furthermore, valuable insights into the influence mechanism nature of Ag@ZIF-8 and Au@ZIF-8 nanocomposites on the electrochemical behaviors are proposed, demonstrating the great potential of the developed sensors for CAP detection.