Carbon nanomaterials, renowned for their exceptional sensitivity and selectivity towards various medical drugs, hold promise as electrode materials for electrochemical biosensors in propofol (PPF) monitoring. However, the issue of fouling has hindered their effective utilization in continuous point-of-care monitoring. In this research, we present a mechanism-driven approach to design a highly sensitive and durable electrochemical sensor tailored for PPF monitoring. We investigated the antifouling mechanism through density functional theory calculations and experiments and found that carboxyl functional groups contribute to the sensitivity and antifouling properties of the electrode. We have uncovered the antifouling ability of different carbon nanomaterials on PPF oxidation products. Factors such as hydrophilicity, geometric morphology, and active surface area played pivotal roles in antifouling. Furthermore, surface modification with hydrophilic polydopamine further enhanced the antifouling effects. In this study, we extensively investigated the electrochemical oxidation of PPF and its oxidation product on carbon nanomaterials, as well as the antifouling mechanism of carbon nanomaterials. The modified electrodes exhibit excellent antifouling performance and stability. This achievement presents a promising approach towards the development of point-of-care PPF analysis in clinical settings.