BACKGROUND: Severe Cushing syndrome is a medical emergency. Etomidate is the only IV option available for treating hypercortisolism, especially in critically ill patients obviating oral medications. METHODS: A systematic review and meta-analysis were conducted on the use of etomidate in the treatment of severe Cushing syndrome. This was registered in PROSPERO, and data reporting was done as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-six published articles comprising 76 clinical cases of 78 clinical episodes of etomidate use were included in the analysis for this review. RESULTS: Etomidate was administered safely to patients with ages ranging from 2 months to 82 years. It served as the first-line treatment in 53.2% of the cases, with 84.3% of patients treated in intensive care unit (ICU) settings. Infusion durations varied from 3 hours to 5.5 months, but 84.8% of treatments were completed in under 2 weeks. Faster cortisol reduction rates were observed in patients with higher baseline cortisol levels ( CONCLUSION: Etomidate is effective and safe for reducing cortisol levels in Cushing syndrome. There is a need for standardized guidelines on etomidate use, including detailed recommendations for different clinical settings and patient conditions to ensure safety and effectiveness.