The aim of this retrospective multicenter observational study is to test the feasibility and safety of a combined extracorporeal CO₂ removal (ECCO₂R) plus renal replacement therapy (RRT) system to use an ultraprotective ventilator setting while maintaining (1) an effective support of renal function and (2) values of pH within the physiologic limits in a cohort of coronavirus infectious disease 2019 (COVID-19) patients. Among COVID-19 patients admitted to the intensive care unit of 9 participating hospitals, 27 patients with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) requiring invasive mechanical ventilation undergoing ECCO₂R-plus-RRT treatment were included in the analysis. The treatment allowed to reduce V_T from 6.0 ± 0.6 mL/kg at baseline to 4.8 ± 0.8, 4.6 ± 1.0, and 4.3 ± 0.3 mL/kg, driving pressure (ΔP) from 19.8 ± 2.5 cm H₂O to 14.8 ± 3.6, 14.38 ± 4.1 and 10.2 ± 1.6 cm H₂O after 24 hours, 48 hours, and at discontinuation of ECCO₂R-plus-RRT (T3), respectively (p < 0.001). PaCO₂ and pH remained stable. Plasma creatinine decreased over the study period from 3.30 ± 1.27 to 1.90 ± 1.30 and 1.27 ± 0.90 mg/dL after 24 and 48 hours of treatment, respectively (p < 0.01). No patient-related events associated with the extracorporeal system were reported. These data show that in patients with COVID-19–induced ARDS and AKI, ECCO₂R-plus-RRT is effective in allowing ultraprotective ventilator settings while maintaining an effective support of renal function and values of pH within physiologic limits.