Enteral immunomodulatory nutrition is suggested as an adjuvant therapy for patients admitted in intensive care units (ICU), but its effectiveness remains debated. The aim of this systematic review and meta-analysis is to examine the effect of dietary immunomodulatory formula on the clinical outcomes and risk of overall mortality in critically ill patients. PubMed, Scopus and ISI web of Knowledge databases were searched until September 2019. Randomized Controlled Trials (RCTs) that used immunomodulatory diet containing omega-3 fatty acid, γ-linolenic acid and antioxidants in ICU were included. Ten RCTs including 1166 participants were included in the meta-analysis. Immunomodulatory diet containing omega-3 fatty acid, γ-linolenic acid and antioxidants led to significantly reduce the duration of ICU stays (WMD: −2.97 days; 95%CI: -5.59, -0.35), duration of mechanical ventilation (WMD = -2.20 days, 95%CI: -4.29, -0.10), SOFA (sequential organ failure assessment) and MOD (multiple organ dysfunction) score (Hedge’s g: -0.42 U/L; 95% CI: -0.74, -0.11). The 28 days’ overall mortality was remarkably decreased following Immunomodulatory supplement in critically ill patients (RR = 0.74, 95% CI: 0.58, 0.91) and extended the ICU- free days (WMD: 4.06 days, 95%CI: 0.02, 8.09). However, immunomodulatory formula had no significant effect on length of hospital stays, ventilator- free days and level of oxygenation.Immunomodulatory diet containing omega-3 fatty acid, γ-linolenic acid and antioxidants might have beneficial effects for the patient’s residing in ICU; However, further well-designed RCTs with larger sample size are recommended to confirmed its effect.