Three-dimensional (3D) printing allows for the design and printing of more complex designs than traditional manufacturing processes. For the manufacture of personalised medicines, such an advantage could enable the production of personalised drug products on demand. In this study, two types of extrusion-based 3D printing techniques, semi-solid syringe extrusion 3D printing and fused deposition modelling, were used to fabricate a combi-layer construct (combi-pill). Two model drugs, tranexamic acid (water soluble, rapid release) and indomethacin (poorly water-soluble, extended release), were printed with different geometries and materials compositions. Fourier transform infrared spectroscopy results showed that there were no interactions detected between drug-drug and drug-polymers. The printed combi-pills demonstrated excellent abrasion resisting properties in friability tests. The use of different functional excipients demonstrated significant impact on in vitro drug release of the model drugs incorporated in two 3D printed layers. Tranexamic acid and indomethacin were successfully 3D printed as a combi-pill with immediate-release and sustained-release profiles, respectively, to target quick anti-bleeding and prolonged anti-inflammation functions. For the first time, this paper systematically demonstrates the feasibility of coupling syringe-based extrusion 3D printing and fused deposition modelling as an innovative platform for various drug therapy productions, facilitating a new era of personalised combi-pills development.