Background: The incidence of myocardial infarction (MI)-related mortality has decreased due to early reperfusion achieved through percutaneous coronary intervention (PCI).Nonetheless, early reperfusion triggers an inflammatory response, causing reperfusion injury that may significantly damage cardiomyocytes. Supersaturated oxygen therapy (SSO2) has recently emerged as a promising adjuvant therapy to overcome this limitation. SSO2 utilizes hyperoxemic oxygen infusate to salvage ischemic tissue by potentially improving coronary microvascular flow after epicardial flow restoration via PCI. Methods: We systematically searched PubMed, ScienceDirect, and Cochrane databases for studies assessing clinical outcomes of SSO2 in patients with MI undergoing PCI. The efficacy endpoint was infarct size, and the safety endpoints included composite major adverse cardiovascular events (MACE), all-cause mortality, reinfarction, and target vessel revascularization. Meta-analyses were performed on included studies. Odds ratios (ORs), mean differences (MDs), and 95% confidence intervals (CIs) were calculated using Review Manager v5.4.1. Results: Four studies, comprising a total of 1,610 patients, were included. In MI patients undergoing PCI, the use of SSO2 significantly reduced infarct size (pooled MD, −4.09; 95% CI, −6.48, −1.70; P < 0.01; I2 = 0%). However, there were no significant differences between SSO2 and PCI-only treatments regarding composite MACE (pooled OR, 0.83; 95% CI, 0.31, 0.97; P = 0.72; I2 = 54%), all-cause mortality (pooled OR, 0.89; 95% CI, 0.10, 8.18; P = 0.91; I2= 59%), reinfarction (pooled OR, 0.82; 95% CI, 0.32, 2.45; P = 0.82; I2 = 0%), or target vessel revascularization (pooled OR, 0.81; 95% CI, 0.33, 1.97; P = 0.64; I2 = 0%). Conclusions Our findings demonstrate that SSO2 therapy may yield promising results by reducing infarct size in MI patients undergoing PCI. Additionally, no safety concerns emerged from the studies included. Further research with larger samples is necessary to confirm our findings and explore potential subpopulations.