Left ventricular assist devices (LVADs) are emerging innovations that provide a feasible alternative treatment for heart failure (HF) patients to enhance their quality of life. In this work, a novel physiological control system to optimize LVAD pump speed using an H-infinity controller was developed. The controller regulates the calculated target pump flow vs. measured pump flow to meet the changes in metabolic demand. The method proposes the implementation of the Frank–Starling mechanism (FSM) approach to control the speed of an LVAD using the left ventricle end-diastolic volume (Vlved) parameter (preload). An operating point was proposed to move between different control lines within the safe area to achieve the FSM. A proportional–integral (PI) controller was used to control the gradient angle between control lines to obtain the flow target. A lumped parameter model of the cardiovascular system was used to evaluate the proposed method. Exercise and rest scenarios were assessed under multi-physiological conditions of HF patients. Simulation results demonstrated that the control system was stable and feasible under different physiological states of the cardiovascular system (CVS). In addition, the proposed controller was able to keep hemodynamic variables within an acceptable range of the mean pump flow (Qp) (max = 5.2 L/min and min = 3.2 L/min) during test conditions.