Surge is a form of dynamic instability created as an unstable pattern in the flow of fluid and can severely affect centrifugal compressor performance by causing fluctuations in flow and pressure parameters. Due to the heavy and costly damage that the surge may cause in various industrial processes such as petrochemical plants, it is necessary to design an appropriate control system to reduce the effect of this phenomenon. The problem of active surge control of a centrifugal compressor using the throttle control valve (TCV) in the presence of compressor parametric uncertainties as well as large demands on upstream and downstream loads is investigated in this work. The control objective was to design a robust control system that can stabilize the compressor over a wide operating range without knowing the upper bound for the uncertainties and load demand. The controller should also react quickly by generating a smooth control signal without saturating the control input. These objectives are achieved by designing a sliding mode controller along with a nonlinear disturbance observer. The performance of the proposed disturbance observer-based controller is evaluated under various operational and load conditions and the results are compared against fuzzy type 1, conventional sliding mode, and wavelet-based neural network robust adaptive controllers. The results show that the proposed method can tolerate large disturbances without any knowledge on the upper bound of the incident disturbance, both on the downstream pressure and upstream mass flow which is highly desirable in practice. The comparative study proves the efficacy of the proposed method using various performance measures. The study also confirms the superior robust performance and stability of the proposed method in front of matched and mismatched disturbances as well as model uncertainties especially close to the instability boundary. Although choosing a TCV actuator has made the control system design easier, the sensitivity of the control valve to flow coefficient and zero calibration under different operating ranges of the compression system is studied carefully and some recommendations for the users are provided.