While numerous sensing strategies have been applied in the determination of Acetaminophen (AP), dopamine (DA), and ascorbic acid (AA), the selectivity is always a critical challenge based on their similar structure and function. Accordingly, the development of a highly selective sensing method is not only necessary but also crucial. In this study, a novel electrochemical sensing platform for the simultaneous determination of AP and DA has been successfully constructed based on a multifunctional nanocomposite (WP6-Pd-COF) of water-soluble pillar[6]arene (WP6), ultrafine Pd nanoparticles, and triethylene glycol-modified covalent organic framework (COF). Pd nanoparticles with an average size of 4.2 nm are prepared by reducing K2PdCl4 under the stabilization of oxygen-rich COF, which shows superior catalytic activity in electrochemical detection. A supramolecular host-guest recognition system introduced between WP6 and analytes (AP, DA, and AA) can effectively recognize AP and DA, implying the simultaneous determination of AP and DA by this approach. The electrode, best operated at a working potential range from -0.2 to 0.8 V (vs. Hg/Hg2Cl2), works in the concentration ranges of 0.2-8 μM for DA and 0.1-7.5 μM for AP, and has a detection limit of 0.06 μM for DA and 0.03 μM for AP (S/N = 3). Therefore, this study presents potential application values in sensing, catalysis, and other fields.