Acute compartment syndrome (ACS) is a well-described condition that merits emergent surgical decompression. Peripheral arterial cannulation can increase the likelihood of ACS in patients requiring extracorporeal membranous oxygen (ECMO). Comorbidities in these critically ill patients may portend negative consequences of decompressive fasciotomy. This study investigated the clinical short-term and mid-term outcomes in pediatric patients with ECMO-associated ACS. This is a retrospective case series at 3 pediatric hospitals from 2006 to 2019, including children ages 0 to 19 years who underwent peripheral arterial cannulation and developed ACS. Eighteen patients developed ACS after receiving peripheral cannulation ECMO. Mean time to diagnosis after cannulation was 63.1 hours. All patients were diagnosed clinically; the most common findings were tight compartments, swelling, and loss of peripheral pulses. Eight patients (44%) died due to underlying illness. Treating physicians decided against decompression for 5 patients due to their underlying illness, instability, and concern for infection. Thirteen patients (72%) underwent decompressive fasciotomies. Ten surgical patients required subsequent surgeries and 6 (33%) developed surgical site infections. Of the 7 surviving surgical patients, 4 (57%) required extremity amputations and 4 had lower extremity neurological deficits on follow-up. Two of 3 nonsurgical patients (66%) had functional lower extremity motor deficits on follow-up. No surviving nonoperative patients developed infections or required amputations. ACS on ECMO is associated with high rates of complications including neurologic deficits, infection, and amputation. Patients treated nonoperatively avoided complications such as infection and amputation, but had more functional neurological deficits than surgical patients. Orthopaedic surgeons should consider the high morbidity of compartment release in these critically ill patients and, with critical care teams, assess whether the potential benefits of surgery outweigh expected risks. Level IV.