Antiplatelet therapy is an attractive treatment option for critically ill patients. However, more evidence on the benefit of this therapy is required. We searched the PubMed and Embase databases from their inception to June 2017 for randomized controlled trials and observational studies that assess the effect of antiplatelet therapy in critically ill patients. Antiplatelet therapy resulted in significant decreases in hospital mortality (risk ratio [RR] 0.81, 95% confidence interval [CI], 0.68–0.97; P = 0. 025), intensive care unit (ICU) mortality (RR 0.78, 95% CI, 0.63–0.97; P = 0. 027), incidence of respiratory distress syndrome or acute lung injury (RR 0.73, 95% CI, 0.58–0.91; P = 0.006), and incidence of sepsis (RR 0.81, 95% CI, 0.68–0.97; P = 0.021). A predefined subgroup analysis according to patient type suggested that hospital mortality and ICU mortality benefits were seen only in septic patients (RR 0.71, 95% CI, 0.58–0.86; P < 0.0001) and (RR 0.65, 95% CI, 0.49–0.86; P = 0.002). By network meta-analysis, the predictive interval plot showed that patients treated with aspirin and clopidogrel had lower risk of hospital mortality as compared with control group. The assessment of rank probabilities using SUCRA plots indicated that aspirin presented the greatest likelihood of having lowest hospital mortality rate. The results of this meta-analysis suggest that antiplatelet therapy is useful for the treatment in critically ill patients, and this is primarily due to an effect on septic patients. Network meta-analysis shows that the probability of being the best antiplatelet therapy for critically ill patients was aspirin.