Background: The incidence, causes and impact of diaphragm thickness evolution in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock are unknown. Our study investigates its evolution during the first week of VA-ECMO and its relationship with sweep gas flow settings.Methods: We conducted a prospective monocentric observational study in a 12-bed ICU in France, enrolling patients on the day of the VA-ECMO implantation. The diaphragm thickness and the diaphragm thickening fraction (as index of contractile activity, dTF; dTF < 20% defined a low contractile activity) were daily measured for one week using ultrasound. Factors associated with diaphragm thickness evolution (categorized as increased, stable, or atrophic based on > 10% modification from baseline to the last measurement), early extubation role (< day4), and patients outcome at 60 days were investigated. Changes in diaphragm thickness, the primary endpoint, was analysed using a mixed-effect linear model (MLM).Results:Of the 29 included patients, seven (23%) presented diaphragm atrophy, 18 remained stable (60%) and 4 exhibited an increase (17%). None of the 13 early-extubated patients experienced diaphragm atrophy, while 7 (46%) presented a decrease when extubated later (p-value = 0.008). Diaphragm thickness changes were not associated with the dTF (p-value = 0.13) but with sweep gas flow (Beta = − 3; Confidence Interval at 95% (CI) [− 4.8; − 1.2]. p-value = 0.001) and pH (Beta = − 2; CI [− 2.9; − 1]. p-value < 0.001) in MLM. The dTF remained low (< 20%) in 20 patients (69%) at the study’s end and was associated with sweep gas flow evolution in MLM (Beta = − 2.8; 95% CI [− 5.2; − 0.5], p-value = 0.017). Odds ratio of death at 60 days in case of diaphragm atrophy by day 7 was 8.50 ([1.4–74], p = 0.029).Conclusion: In our study, diaphragm thickness evolution was frequent and not associated with the diaphragm thickening fraction. Diaphragm was preserved from atrophy in case of early extubation with ongoing VA-ECMO assistance. Metabolic disorders resulting from organ failures and sweep gas flow were linked with diaphragm thickness evolution. Preserved diaphragm thickness in VA-ECMO survivors emphasizes the importance of diaphragm-protective strategies, including meticulous sweep gas flow titration.