Background: Cardiogenic shock (CS) carries high mortality. The roles of specific mechanical circulatory support (MCS) systems are unclear. We compared the clinical outcomes of Impella versus extracorporal membrane oxygenation (ECMO) in patients with CS. Methods: This is a systematic review and meta-analysis that was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. We searched PubMed, Cochrane Central Register, Embase, Web of Science, Google Scholar, and ClinicalTrials.gov (inception through May 10, 2022) for studies comparing the outcomes of Impella versus ECMO in CS. We used random-effects models to calculate risk ratios (RRs) with 95% confidence interval (CIs). End points included in-hospital, 30-day, and 12-month all-cause mortality, successful weaning from MCS, bridge to transplant, all reported bleeding, stroke, and acute kidney injury. Results: A total of 10 studies consisting of 1,827 CS patients treated with MCS were included in the analysis. The risk of in-hospital all-cause mortality was significantly lower with Impella compared with ECMO (RR, 0.80; 95% CI, 0.65–1.00; P = 0.05), whereas there was no statistically significant difference in 30-day (RR, 0.97, 95% CI, 0.82–1.16; P = 0.77) and 12-month mortality (RR, 0.90; 95% CI, 0.74–1.11; P = 0.32). There were no significant differences between the two groups in terms of successful weaning (RR, 0.97; 95% CI, 0.81–1.15; P = 0.70) and bridging to transplant (RR, 0.88; 95% CI, 0.58–1.35; P = 0.56). There was less risk of bleeding and stroke in the Impella group compared with the ECMO group. Conclusions: In patients with CS, the use of Impella is associated with lower rates of in-hospital mortality, bleeding, and stroke than ECMO. Future randomized studies with adequate sample sizes are needed to confirm these findings.