The dynamics of a quadruple tank system (QTS) represent an extensive class of multivariate nonlinear uncertain systems found in the industry. It has been established that changes in split fractions affect the transmission zero location, thereby altering the operating conditions between the minimum and non-minimum phase regions. The latter is difficult to control as more fluid flows into the two upper tanks than into the two bottom tanks, resulting in competing effects between the initial and final system responses. This attribute, alongside nonlinearity, uncertainties, constraints, and a multivariate nature, can degrade closed-loop system performance, leading to instability. In this study, we addressed the aforementioned challenges by designing controllers for the regulation of the water flow in the two bottom tanks of the QTS. For comparative analysis, three controller algorithms—a nonlinear model predictive controller (NMPC), NMPC augmented with an extended Kalman filter (i.e., NMPC-EKF) and linear model predictive controller (LMPC)—were considered in the analysis and design of the control mechanism for the quadruple water level system in a non-minimum phase condition via the Matrix Laboratory (MATLAB) simulation package environment. The simulated and real-time results in the closed loop were analyzed, and the controller performances were considered based on faster setpoint responses, less oscillation, settling time, overshoot, and smaller integral absolute error (IAE) and integral square error (ISE) under various operational conditions. The study showed that the NMPC, when augmented with an EKF, is effective for the control of a QTS in the non-minimum phase and could be designed for more complex, nonlinear, and multivariable dynamics systems, even in the presence of constraints.