In this work, the design, microstructures and mechanical properties of five novel non-equiatomic lightweight medium entropy alloys were studied. The manufactured alloys were based on the Al65Cu5Mg5Si15Zn5X5 and Al70Cu5Mg5Si10Zn5X5 systems. The formation and presence of phases and microstructures were studied by introducing Fe, Ni, Cr, Mn and Zr. The feasibility of CALPHAD method for the design of new alloys was studied, demonstrating to be a good approach in the design of medium entropy alloys, due to accurate prediction of the phases, which were validated via X-ray diffraction and scanning electron microscopy with energy dispersive spectroscopy. In addition, the alloys were manufactured using an industrial-scale die-casting process to make the alloys viable as engineering materials. In terms of mechanical properties, the alloys exhibited moderate plastic deformation and very high compressive strength up to 644 MPa. Finally, the reported microhardness value was in the range of 200 HV0.1 to 264 HV0.1, which was two to three times higher than those of commercial Al alloys.