Previous studies stated that high oxygen supply in patients with myocardial infarction (MI) was not associated with improved outcomes. However, the particularities of ST-elevation myocardial infarction (STEMI) and the results of a recent trial raised the question if this subgroup of patients benefits from high oxygen supply. This study aims to evaluate the clinical effect of high oxygen supply in patients with STEMI using a systematic review of the available literature. All randomized controlled trials (RCTs) evaluating the systematic use of high oxygen (6 L/min or higher) versus room air or lower oxygen supply in STEMI patients were included. Systematic review with meta-analysis of trials retrieved in July 2020. Six databases were searched. The confidence in the pooled estimates was ascertained through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Risk of bias was evaluated using the Cochrane risk of bias tool. There were five eligible RCTs (7703 patients). High oxygen supply was associated with a significant risk reduction of short-term mortality [risk ratio (RR) 0.83; 95% confidence interval (CI), 0.70-0.98; I = 0%]. Mortality (longest follow-up) (RR 0.83; 95% CI, 0.71-0.97; I = 0%) and heart failure (RR 0.84; 95% CI, 0.60-1.18; I = 0%) did not present a risk reduction. Recurrent MI presented a contradictory result, favouring the lower oxygen protocol (RR 1.47; 95% CI, 0.84-2.56; I = 0%). The GRADE analysis was very low. High oxygen supply may be associated with a decrease in short-term mortality in STEMI patients, but the pooled data are not robust enough to allow definitive conclusions.