In this paper, we present the design, the implementation and the validation of a novel Internet of Things (IoT) drug monitoring system for the online continuous and simultaneous detection of two main anesthetics, e.g., propofol and paracetamol, in undiluted human serum. The described full system consists of a custom-built electronic Raspberry Pi (RPi) based Printed Circuit Board (PCB) that drives and reads out the signal from an electrochemical sensing platform integrated into a fluidic system. Thanks to the Polydimethylsiloxane (PDMS) fluidic device, the analyzed sample is automatically fluxed on the sensing site. The IoT network is supported by a Cloud system, which allows the doctor to control and share all the patient’s data through a dedicated Android application and a smart watch. The validation closes with the first ever demonstration that our system successfully works for the simultaneous monitoring of propofol and paracetamol in undiluted human serum by measuring the concentration trends of these two drugs in fluxing conditions over time.