With the advances in new materials, equipment, and processes, additive manufacturing (AM) has gained increased importance for producing the final parts that are used in several industrial areas, such as automotive, aeronautics, and health. The constant development of 3D-printing equipment allows for printing multi-material systems as sandwich specimens using, for example, double-nozzle configurations. The present study aimed to compare the mechanical behavior of multi-material specimens that were produced using a double-nozzle 3D printer. The materials that were included in this study were the copolymer acrylonitrile-butadiene-styrene (ABS), high-impact polystyrene (HIPS), poly(methyl methacrylate) (PMMA), and thermoplastic polyurethane (TPU). The configuration of the sandwich structures consisted of a core of TPU and the outer skins made of one of the other three materials. The mechanical behavior was evaluated through three-point bending (3PB) and transverse impact tests and compared with mono-material printed specimens. The effect of aging in artificial saliva was evaluated for all the processed materials. The main conclusion of this study was that the aging process did not significantly alter the mechanical properties for mono-materials, except for PMMA, where the maximum flexural stress decreased. In the sandwich structures, the TPU core had a softening effect, inducing a significant increase in the resilience and resistance to transverse impact. The obtained results are quite promising for applications in biomedical devices, such as protective mouthguards or teeth aligners. In these specific applications, the changes in the mechanical properties with time and with the contact of saliva assume particular importance.