Mild cases of drug induced rhabdomyolysis are well documented, however severe cases require additional investigation. Here, we report a case of a 40-year-old female with no pertinent medical history who presented to the emergency department with bilateral leg weakness after recent polysubstance use. During the 26 days of hospitalization, the patient had three days of sustained creatine phosphokinase level of >42,000 U/L, oliguric acute renal failure treated with emergent dialysis, compartment syndrome requiring bilateral thigh and leg fasciotomies and required discharge to a long-term hemodialysis rehab center for ongoing management. The patient was diagnosed with a rare and life-threatening complication of methamphetamine (MA)-induced rhabdomyolysis. The relationship between MA-induced rhabdomyolysis and compartment syndrome is far from a novel concept. However, nearly all published cases demonstrate mild kidney injury and precipitating factors of agitated delirium and hyperpyrexia as the driving force for the compartment syndrome. In this report, we present a successfully treated, severe case of MA-induced kidney failure and rhabdomyolysis leading to compartment syndrome without clear indications of psychomotor agitation and hyperpyrexia. This report aims to highlight the importance of quick recognition of a rare methamphetamine side effect and the need for hasty response to limit complications and decrease hospital stay. Perhaps in the future, rhabdomyolysis etiology and severity may drive specific treatment plans.