Background Septic shock is considered as a subset of sepsis in which there is marked cellular and circulatory impairment that is associated with higher mortality. It is important to differentiate septic shock from cardiovascular dysfunction and to recognize the effects of cellular abnormalities. The task force stated that there is an agreement that patients who develop septic shock are predicted to have more severe illness with a higher percentage of mortality than having sepsis alone.Objective To evaluate the use of a hemodynamic optimization protocol using a ventricular arterial coupling-guided approach for critically ill patients with septic shock.Patients and methods This randomized controlled trial was conducted on 100 adult patients who were admitted to the units of the Department of Critical Care Medicine, Alexandria Main University Hospital, with a diagnosis of septic shock requiring mechanical ventilation for 6 months from January 1, to the June 30, 2019.Results The results of this study demonstrated significant hemodynamic improvement for the HEMOVACS group. This was illustrated by an increase in mean arterial blood pressure and cardiac output and a decline in serum lactate without an effect on 28-day mortality. The effect of applying the HEMOVACS protocol was preliminarily encouraging, although it was applied for only a single time, at the time of diagnosis.Conclusion Early initiation of this protocol at the time of diagnosing septic shock and for follow-up and monitoring may provide better outcomes for patients with septic shock.