The early diagnosis of major diseases such as cancer is typically a major issue for humanity. Human α-fetoprotein (AFP) as a sialylated glycoprotein is of approximately 68 kD molecular weight and is considered to be a key biomarker, and an increase in its level indicates the presence of liver, testicular, or gastric cancer. In this study, an electrochemical AFP immunosensor based on Fe 3 O 4 NPs@covalent organic framework decorated gold nanoparticles (Fe 3 O 4 NPs@COF/AuNPs) for the electrode platform and double-coated magnetic nanoparticles (MNPs) based on SiO 2 @TiO 2 (MNPs@SiO 2 @TiO 2 ) nanocomposites for the signal amplification was fabricated. The immobilization of anti-AFP capture antibody was successfully performed on Fe 3 O 4 NPs@COF/AuNPs modified electrode surface by amino-gold affinity, while the conjugation of anti-AFP secondary antibody on MNPs@SiO 2 @TiO 2 was achieved by the electrostatic/ionic interactions. Transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) analysis, cyclic voltammetry (CV), square wave voltammetry (SWV), and electrochemical impedance spectroscopy (EIS) techniques were used to characterize the nanostructures in terms of physical and electrochemical features. The limit of detection (LOD) was 3.30 fg mL −1 . The findings revealed that the proposed electrochemical AFP immunosensor can be effectively used to diagnose cancer.