Background: Liberation from sedation may be beneficial for patients with acute respiratory distress syndrome supported by veno-venous (VV) extracorporeal membrane oxygenation (ECMO). Currently, there is limited evidence to support this approach. Therefore, this study aimed to compare the 90-day patient mortality of different sedation strategies in COVID-19 patients supported with VV ECMO. Methods: Retrospective, observational sub-study of the COVID-19 Critical Care Consortium database including COVID-19 patients supported with VV ECMO. Two cohorts were compared: high sedation patients who received neuromuscular blocking agents (NMBAs) throughout ECMO and low sedation patients who did not receive NMBA consistently. Patients’ level of sedation during ECMO was also considered. The primary outcome was 90-day in-hospital mortality and was assessed using cause-specific Cox proportional hazard models. Results: 224 low and 104 high sedation patients were included. Pre-ECMO respiratory condition prior was similar between groups, except for the ratio of partial pressure of oxygen to inspired fraction of oxygen, which was lower in the high sedation group at 93 [61–130] than the low sedation group at 106 [69–140]. No difference was observed in disease severity scores between cohorts. Low sedation patients had longer ECMO runs, more circuit changes, but lower infectious and hemorrhagic complications. Higher sedation was associated with a hazard ratio for death of 3.23 (95% CI 2.16–4.83) compared to low sedation. Conclusions: Reduced sedation in COVID-19 ECMO patients is feasible and may be associated with improved survival and reduced complications compared to continuous paralysis, albeit with longer ECMO runs.