Thermoplastic fibre metal laminates (FMLs) increasingly attract attention in manufacturing parts that must present high strength-to-weight and stiffness-to-weight ratios. In addition, their polymer matrix's recyclability meets sustainability needs that conventional thermosetting-based FMLs cannot encounter. Mechanical drilling is one of the most used manufacturing operations they are subjected to, but it can still be a source of damage in the drilled zone, which, in turn, can impair the part service performance. In particular, the interface conditions between the metal skins and composite core significantly determine the drilling performance. In this framework, the paper investigates how the metal sheet surface modification treatments and composite polymer matrix characteristics can affect the drilling operation performance. It has been proved that rough metal surfaces and a polymer matrix with enhanced thermal resistance are the best combinations to ensure the integrity and quality of drilled holes.