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Background: Patients with severe respiratory failure due to COVID‐19 who are not under mechanical ventilation may develop severe hypoxemia when complicated with spontaneous pneumomediastinum (PM). These patients may be harmed by invasive ventilation. Alternatively, veno‐venous (V‐V) extracorporeal membrane oxygenation (ECMO) may be applied. We report on the efficacy of V‐V ECMO and invasive ventilation as initial advanced respiratory support in patients with COVID‐19 and acute respiratory failure due to spontaneous PM. Methods: This was a retrospective cohort study performed between March 2020 and January 2022. Enrolled patients had COVID‐19 and acute respiratory failure due to spontaneous PM and were not invasively ventilated. Patients were treated in the intensive care unit (ICU) with invasive ventilation (invasive ventilation group) or V‐V ECMO support (V‐V ECMO group) as the main therapeutic option. The primary outcomes were mortality and ICU discharge at 90 days after ICU admission. Results: Twenty‐two patients were included in this study (invasive ventilation group: 13 [59%]; V‐V ECMO group: 9 [41%]). The V‐V ECMO strategy was significantly associated with lower mortality (hazard ratio [HR] 0.33 [95% CI 0.12–0.97], p = 0.04). Five (38%) patients in the V‐V ECMO group were intubated and eight (89%) patients in the invasive ventilation group required V‐V ECMO support within 30 days from ICU admission. Three (33%) patients in the V‐V ECMO group were discharged from ICU within 90 days compared to one (8%) patient in the invasive ventilation group (HR 4.71 [95% CI 0.48–45.3], p = 0.18). Conclusions: Preliminary data suggest that V‐V ECMO without invasive ventilation may improve survival in COVID‐19‐related acute respiratory failure due to spontaneous PM. The study's retrospective design and limited sample size underscore the necessity for additional investigation and warrant caution. [ABSTRACT FROM AUTHOR]