Physical therapy (PT) utilization in patients requiring mechanical circulatory support (MCS) and extracorporeal membrane oxygenation (ECMO) has been reported; however, little is known about intensive rehabilitation and associated outcomes in patients requiring extended complex MCS and/or ECMO support. Authors sought to explore safety, feasibility and outcomes associated with active rehabilitation in patients requiring prolonged advanced MCS/ECMO support. Single-center retrospective series evaluated functional, clinical, and longitudinal outcomes of sample of eight critically ill, adult (≥18 years of age) patients who underwent a intensive rehabilitation while receiving prolonged MCS/ECMO through advanced configurations including: venovenous (VV-ECMO), venoarterial (VA-ECMO), oxygenator with right ventricular assist device (Oxy-RVAD) and right ventricular assist device (RVAD). 406 sessions were conducted; 246 during provision of advanced MCS/ECMO support. Incidence of major adverse events-accidental decannulation, migration of cannulas, circuit failure, hemorrhage, major flow limitations, and major hemodynamic instability-was 1.2 events per 100 sessions. None of reported major adverse events impeded longitudinal ability to participate in PT. Increased time to PT initiation was associated with a statistically significant increase in intensive care unit (ICU) length-of-stay (β1 1.93, CI 0.55-3.30) and reduced ambulatory distance during last session on MCS/ECMO (β1 -47.64, CI - 93.93, -1.66). All patients survived to hospital discharge and 12 months from sentinel hospitalization. Amongst those patients discharged to an inpatient rehabilitation center (n = 4), all were discharged home within 3 months. Findings support the safety and feasibility of active rehabilitational PT in patients requiring extended durations of advanced MCS/ECMO support. Moreover, it highlights potentially associated benefits of this degree of intensive rehabilitation for these unique patients. Further investigation is needed to identify associations with longitudinal clinical outcomes, as well as predictors of success in this population.