In this work, we present a novel electrochemical cleaning procedure for long-term electrochemical monitoring of propofol by using boron-doped diamond (BDD) and pencil graphite electrode (PGE). Propofol is an anesthetic that is widely used for long-lasting medical operations. Therefore, it is of great importance to be able to develop a sensor for long-term detection of propofol in the therapeutic range. Up to now, this aim could not be achieved due to loss of sensor sensitivity caused by the fouling phenomenon from propofol oxidation mechanism. We have developed intermittent cleaning steps to be able to ensure sensitive detection of propofol for more than 4 h. In addition to long-term monitoring, we also managed to detect the drug inside human serum by using PGE for differential pulse voltammetry (DPV) measurements achieving a limit of detection (LOD) of 0.82 ± 0.08 μM, which is even lower that the physiological concentration usually used range of propofol ([1–60] μM).