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Sepsis has remained a high mortality rate worldwide. Endothelial cell dysfunction is closely associated with the development of sepsis. Hydrocortisone has potent immunological and antitoxic effects, and thus it is frequently used in the treatment of septic shock. However, it can also cause respiratory damage and death by anaphylaxis. In recent years, the combination of hydrocortisone and other drugs such as vitamin C and thiamine has achieved promising outcomes in refractory septic shock. The present review focuses on the therapeutic effects of hydrocortisone in sepsis and summarizes the mechanisms by which hydrocortisone acted on the vascular endothelial cells. We highlighted the effect of hydrocortisone on anti-inflammation, anti-apoptosis, improvement of vascular functions, and anti-oxidative stress. We also pointed out that the mechanisms by which the combination therapy with other drugs enhances the effects of hydrocortisone are still unclear and need to be clarified to determine the benefit of the treatment of sepsis.