An electrochemical and colorimetric dual-mode sensor is developed for the detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein (S protein). Pt nanoclusters (PtNCs) are successively decorated with 4-mercaptophenylboric acid (4-MPBA), S protein templates and poly(ionic liquids), and the surface molecularly imprinted PtNCs are obtained after the S protein templates are removed in acidic media. The rebinding of S protein can cause distinct changes in the electrochemical impedance spectroscopy (EIS) of the PtNCs, achieving sensitive electrochemical detection of S protein. In addition, the peroxidase-like activity of the PtNCs nanozyme is shielded after the rebinding of S protein, resulting in distinct changes in the color/visible spectra of 3,3',5,5'-tetramethylbenzidine (TMB) + hydrogen peroxide (H2O2), and thus colorimetric detection of S protein is achieved. The linear range for S protein detecting is 1 pg mL−1 ~ 1 μg mL−1, and the limits of detection for electrochemical and colorimetric method are 0.36 pg mL−1 and 0.57 pg mL−1, respectively. The developed dual-mode sensor shows high specificity and stability for S protein, and its reliability is also demonstrated by the detection of S protein in clinical serum sample.