This paper investigates the performance achievable with a fractional-order PID regulator controlling the Depth of Hypnosis (measured via the Bispectral Index Scale) through the administration of propofol during the maintenance phase of total intravenous anesthesia. In particular, two different methodologies were applied to tune the controller: in the first case, genetic algorithms (GAs) were used to minimize the integrated absolute error, while in the second case, the isodamping approach—a method that targets phase margin invariance with respect to the process dc gain—was employed. In both cases, the performance was extensively analyzed and compared with that of a standard PID controller by simulating multiple patients through a Monte Carlo method. The results demonstrate that a fractional-order PID controller can be effectively used to control the Depth of Hypnosis, but the improvement with respect to a standard PID controller is marginal.