Our primary objective was to identify if fasciotomy was associated with increased mortality in patients who developed acute compartment syndrome (ACS) on extracorporeal cardiopulmonary resuscitation (ECPR). Additionally, we sought to identify any additional risk factors for mortality in these patients and report the amputation-free survival following fasciotomy. We retrospectively reviewed adult ECPR patients from the Extracorporeal Life Support Organization registry who were diagnosed with ACS between 2013 and 2021. Of 764 ECPR patients with limb complications, 127 patients (17%) with ACS were identified, of which 78 (63%) had fasciotomies, and 14 (11%) had amputations. Fasciotomy was associated with a 23% rate of amputation-free survival. There were no significant differences in demographics or baseline laboratory values between those with and without fasciotomy. Overall, 88 of 127 (69%) patients with ACS died. With or without fasciotomy, the mortality of ACS patients was similar, 68% vs. 71%. Multivariable logistic regression demonstrated that body mass index (BMI; adjusted odds ratio [aOR] = 1.22, 95% confidence interval [CI] = 1.01–1.48) and 24 hour mean blood pressure (BP; aOR = 0.93, 95% CI = 0.88–0.99) were independently associated with mortality. Fasciotomy was not an independent risk factor for mortality (aOR = 0.24, 95% CI = 0.03–1.88). The results of this study may help guide surgical decision-making for patients who develop ACS after ECPR. However, the retrospective nature of this study does not preclude selection bias in patients who have received fasciotomy. Thus, prospective studies are necessary to confirm these findings.