Continuous monitoring of anaesthetics infusion is demanded by anaesthesiologists to help in defining personalized dose, hence reducing risks and side effects. We propose the first piece of technology tailored explicitly to close the loop between anaesthesiologist and patient with continuous drug monitoring. Direct detection of drugs is achieved with electrochemical techniques, and several options are present in literature to measure propofol (widely used anaesthetics). Still, the sensors proposed do not enable in-situ detection, they do not provide this information continuously, and they are based on bulky and costly lab equipment. In this paper, we present a novel smart pen-shaped electronic system for continuous monitoring of propofol in human serum. The system consists of a needle-shaped sensor, a quasi digital front-end, a smart machine learning data processing, in a single wireless battery-operated embedded device featuring Bluetooth Low Energy (BLE) communication. The system has been tested and characterized in real, undiluted human serum, at 37 ∘ C. The device features a limit of detection of 3.8 μ M, meeting the requirement of the target application, with an electronics system 59% smaller and 81% less power consuming w.r.t. the state-of-the-art, using a smart machine learning classification for data processing, which guarantees up to twenty continuous measure.