Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used as mechanical circulatory support in cardiogenic shock (CS). It restores peripheral perfusion, at the expense of increased left ventricle (LV) afterload. In this setting, Impella can be used as direct unloading strategy. Aim of this meta-analysis was to investigate efficacy and safety of LV unloading with Impella during ECMO in CS. A systematic search on Medline, Scopus and Cochrane Library was performed using as combination of keywords: extracorporeal membrane oxygenation, Impella, percutaneous micro axial pump, ECPELLA, cardiogenic shock. We aimed to include studies, which compared the use of ECMO with and without Impella (ECPELLA vs. ECMO). Primary endpoint was short-term all-cause mortality; secondary endpoints included major bleeding, haemolysis, need for renal replacement therapy (RRT) and cerebrovascular accident (CVA). Five studies met the inclusion criteria, with a total population of 972 patients. The ECPELLA cohort showed improved survival compared to the control group (RR (Risk Ratio): 0.86; 95% CI (Confidence Interval): 0.76, 0.96; p = 0.009). When including in the analysis only studies with homogeneous comparator groups, LV unloading with Impella remained associated with significant reduction in mortality (RR: 0.85; 95% CI: 0.75, 0.97; p = 0.01). Haemolysis (RR: 1.70; 95% CI: 1.35, 2.15; p < 0.00001) and RRT (RR: 1.86; 95% CI: 1.07, 3.21; p = 0.03) occurred at a higher rate in the ECPELLA group. There was no difference between the two groups in terms of major bleeding (RR: 1.37; 95% CI: 0.88, 2.13; p = 0.16) and CVA (RR: 0.91; 95% CI: 0.61, 1.38; p = 0.66). In conclusion, LV unloading with Impella during ECMO was associated with improved survival, despite increased haemolysis and need for RRT, without additional risk of major bleeding and CVA.