(1) Background: Acute kidney injury (AKI) is a common but under-investigated complication in patients receiving extracorporeal membrane oxygenation (ECMO). We aimed to define the incidence and clinical course, as well as the predictors of AKI in adults receiving ECMO support. (2) Materials and Methods: This is a retrospective analysis of all patients undergoing veno-venous ECMO treatment in a tertiary care center between December 2008 and December 2017. The primary endpoint was the new occurrence of an AKI of stage 2 or 3 according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification after ECMO implantation. (3) Results: During the observation period, 103 patients underwent veno-venous ECMO implantation. In total, 59 patients (57.3%) met the primary endpoint with an AKI of stage 2 or 3 and 55 patients (53.4%) required renal replacement therapy. Patients with an AKI of 2 or 3 suffered from more bleeding and infectious complications. Whereas weaning failure from ECMO (30/59 (50.8%) vs. 15/44 (34.1%), p = 0.08) and 30-day mortality (35/59 (59.3%) vs. 17/44 (38.6%), p = 0.06) only tended to be higher in the group with an AKI of stage 2 or 3, long-term survival of up to five years was significantly lower in the group with an AKI of stage 2 or 3 (p = 0.015). High lactate, serum creatinine, and ECMO pump-speed levels, and low platelets, a low base excess, and a low hematocrit level before ECMO were independent predictors of moderate to severe AKI. Primary hypercapnic acidosis was more common in AKI non-survivors (12 (32.4%) vs. 0 (0.0%), p < 0.01). Accordingly, pCO₂-levels prior to ECMO implantation tended to be higher in AKI non-survivors (76.12 ± 27.90 mmHg vs. 64.44 ± 44.31 mmHg, p = 0.08). In addition, the duration of mechanical ventilation prior to ECMO-implantation tended to be longer (91.14 ± 108.16 h vs. 75.90 ± 86.81 h, p = 0.078), while serum creatinine (180.92 ± 115.72 mmol/L vs. 124.95 ± 77.77 mmol/L, p = 0.03) and bicarbonate levels were significantly higher in non-survivors (28.22 ± 8.44 mmol/L vs. 23.36 ± 4.19 mmol/L, p = 0.04). (4) Conclusion: Two-thirds of adult patients receiving ECMO suffered from moderate to severe AKI, with a significantly increased morbidity and long-term mortality.