To develop tailored and performing biodegradable multilayer systems with polyester as cap layers and thermoplastic starch (TPS)/polyester blends in the core, several TPS-based blends, with varying formulations and several biodegradable and potentially biobased polyesters, were first elaborated. Poly(butylene adipate-co-terephthalate) (PBAT), poly(butylene succinate) (PBS) and poly(butylene succinate-co-adipate) (PBSA) were tested. The TPS-based blends for the core layer were compatibilized with a multifunctional epoxide styrene-acrylic reactive chain extender. As evidenced by tensile tests, the compatibilization was more effective with blends based on PBAT, probably due to its higher number of reactive chain ends. Multilayer films comprising neat PBAT cap layers and a TPS/PBAT blend, compatibilized or not, as a core layer were then elaborated by coextrusion. Thanks to the PBAT cap layers, the multilayer films had improved thermal stability and water vapor barrier properties, while TPS in the core layer added oxygen barrier properties to the global systems. In connection with the applications, the biocompatibility was also demonstrated through cell growth tests. The suitability of such multilayer films for biodegradable packaging linked to biomedical applications was thereby confirmed.