This study investigates the influence of using multifunctional epoxy Joncryl ADR 4468 chain extender (CE) on the properties of various polylactide (PLA)/thermoplastic polyurethane (TPU) (75 wt/25 wt) blend systems. The blends were based on two different TPU grades with ether- and ester-based soft segment as the dispersed phase (i.e., TPUether and TPUester) and an amorphous and a semicrystalline PLA grades as the matrix (i.e., aPLA and scPLA). PLA appeared to be more compatible with the TPUester, which caused the enhancement of the impact strength and strain at break values of the blends more remarkably. The dynamic rheological experiments also confirmed that the CE revealed a better reactivity with TPUester than TPUether. This further enhanced the interfacial compatibility between the PLA and TPUester and thereby dramatically improved the impact strength and ductility of the PLA/TPUester blends, specifically those with 0.5 wt% CE. Meanwhile, aPLA as the matrix reflected the TPUs toughening effect more efficiently than scPLA. This was due to the possible shrinkage caused by the crystallization of scPLA matrix, which could deteriorate the interfacial interactions between the phases in the corresponding blends.