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With the worsening opioid epidemic in America, more patients are developing found down extremity compartment syndrome (FDECS). The purpose of this study was to describe this patient population, including their presenting symptoms, laboratory test results, and clinical outcomes. Methods We performed a 2-center retrospective review of adult patients who developed FDECS secondary to substance use from January 2006 to December 2019. Patients were managed operatively or nonoperatively at the surgeon's discretion. Data on patient demographic characteristics, laboratory values, hospital course, and clinical outcomes were collected from electronic medical records. Results In this study, 91 patients were included: 85 patients were managed operatively, and 6 patients were managed nonoperatively. Most patients were male, and the mean patient age (and standard deviation) was 37 ± 11 years. Opioids were the most common substance used. Patients managed operatively underwent a mean of 4 ± 3 surgical procedures, 44% received a skin graft, 25% developed a wound infection, and 11% underwent limb amputation. Patients managed nonoperatively did not undergo a subsequent fasciotomy or amputation. At a mean follow-up of 2.3 years, persistent weakness (66%), pain (78%), persistent sensory deficits (53%), and contractures (18%) were common. Conclusions Patients who develop FDECS secondary to substance use have high surgical complication rates and poor clinical outcomes. We found high rates of wound infection, revision surgical procedures, and amputation, often leaving young adults with lifelong disability. Level of Evidence Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.