In this Article, we studied the enzymatic hydrolytic biodegradation behavior of a novel multiblock thermoplastic polyurethane (TPU) system, which incorporates polyhedral oligomeric silsesquioxane (POSS) into linear biodegradable thermoplastic polyurethanes containing poly(epsilon-caproactone) (PCL) and polyethylene glycol (PEG) blocks. The biodegradation behavior of POSS-PCL-PEG TPUs was characterized by proton nuclear magnetic resonance spectroscopy (H-1 NMR), differential scanning calorimetry (DSC), tensile tests, scanning electron microscopy (SEM), and wavelength dispersive X-ray spectrometry (WDS) after enduring 22-day accelerated enzymatic hydrolytic degradation tests. POSS incorporation significantly suppressed in vitro enzymatic hydrolytic degradation of PCL-PEG-based multiblock TPUs by a surface passivation mechanism. WDS observations revealed that the covalently bonded POSS moieties developed a near-continuous and robust POSS-layer after initial degradation, which prevented ester bonds of PCL from enzymatic attack, thereby inhibiting further degradation. These striking results provide a new strategy to fabricate the polyester-based biostable thermoplastic polyurethanes (TPUs) of potential use in long-term surgical implants.