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Objectives This prospective, comparative and randomised clinical study evaluated the effectiveness of triple therapy regimen (hydrocortisone, thiamine and vitamin C) versus hydrocortisone alone in reducing the mortality rate and preventing progressive organ dysfunction in septic shock patients. Methods A total of 94 patients were randomly assigned to one of two groups: the first group received hydrocortisone 50 mg/6‐h IV for 7 days or till intensive care unit (ICU) discharge, if sooner, followed by tapering. The second group received hydrocortisone 50 mg/6‐h IV for 7 days or ICU discharge followed by tapering, vitamin C 1.5 g/6‐h IV for 4 days or till ICU discharge and thiamine 200 mg/12‐h IV for 4 days or till ICU discharge. Results The triple therapy regimen showed a non‐significant reduction in 28‐day mortality compared to hydrocortisone alone (17 [36.2%] vs. 21 [44.7%]; P = .4005), but it was significantly lower than the control group regarding shock time and the duration of vasopressor use in days (4.000 [3.000‐7.000]; 5.000 [4.000‐8.000], [P = .0100]). The patients in the control group were likely to get 0.59 more in SCr level than those in the intervention group by a linear regression model which was significant (P < .05). Also, the number of patients who developed a fever after 216 hours was significantly higher in the control group (P value = .0299). Conclusion Vitamin C, thiamine, and hydrocortisone regimen for septic shock management showed non‐significant efficacy in decreasing 28‐day mortality when compared to hydrocortisone monotherapy. On the other hand, it showed significant efficacy in decreasing the shock time and duration on vasopressors.