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Background: Enteral immunomodulatory nutrition is recommended as an adjuvant therapy for patients in intensive care units (ICU), but its effectiveness is incompletely understood. Aim: The aim of this review was to examine the effect of a commonly used immunomodulatory formula—omega‐3 fatty acids, γ‐linolenic acid, and antioxidants—on clinical outcomes and mortality risk in critically ill patients. Design: Systematic review and meta‐analysis of randomized controlled trials (RCTs). Method: PubMed, Scopus, and Institute for Scientific Information (ISI) Web of Knowledge databases were searched until 18 February 2021. RCTs that used the immunomodulatory formula in the ICU were included. Results: Ten RCTs (1166 participants) were included in the meta‐analysis. The immunomodulatory formula reduced the duration of ICU stay weighted mean difference [(WMD): −2.97 days; 95%CI: −5.59, −0.35)], mechanical ventilation (WMD = −2.20 days, 95%CI: −4.29, −0.10), sequential organ failure assessment and multiple organ dysfunction scores (Hedge's g: −0.42 U/L; 95% CI: −0.74, −0.11), decreased 8‐day overall mortality risk (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). The improvement in respiratory function and reduction in mortality risk was more in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Furthermore, the reduction in mechanical ventilation and mortality risk was more evident in older (>60 years) vs young adults. Conclusion and Relevance to Clinical Practice: Taken together, the immunomodulatory formula may enhance clinical practice for critical care nurses, such that the prevalence and/or susceptibility to secondary conditions commonly encountered in the ICU (ie, ALI and ARDS) could be attenuated, ultimately allowing critical care nurses to focus their care on the primary reason for which a patient is in the ICU. The study protocol was registered in PROSPERO. [ABSTRACT FROM AUTHOR]