This work reports how novel multi-layered (from double-layered to quadruple-layered) microparticles comprising immiscible polymers can be fabricated through a simple, economical, reliable and versatile one-step solvent evaporation method. These multi-layered microparticles would be excellent candidates to overcome problems inherent in single-layered microparticles for drug delivery. Particle morphologies, layer configurations, and drug distribution were determined by scanning electron microscopy and Raman mapping. Key process parameters achieving the formation of the multi-layered structure were identified. Encapsulation of multiple drugs and layer localization of these drugs within these multi-layered microparticles have also shown to be possible, which were driven by drug-polymer affinity. This one-step fabrication technique can therefore be used for tailoring particle designs, thus facilitating the development of multiparticulate drug delivery devices.