Separation and enrichment of target cells prior to downstream analyses is an essential pre-treatment step in many biomedical and clinical assays. Separation techniques utilizing simple, cost-effective, and user-friendly devices are highly desirable, both in the lab and at the point of need. Passive microfluidic approaches, especially inertial microfluidics, fit this brief perfectly and are highly desired. Using an optimized additive manufacturing technique, we developed a zigzag microchannel for rigid inertial separation and enrichment, hereafter referred to as Z-RISE. We empirically showed that the Z-RISE device outperforms equivalent devices based on curvilinear (sinusoidal), asymmetric curvilinear, zigzag with round corners, or square-wave formats and modelled this behavior to gain a better understanding of the physics underpinning the improved focusing and separation performance. The comparison between rigid and soft zigzag microchannels reveals that channel rigidity significantly affects and enhances the focusing performance of the microchannel. Compared to other serpentine microchannels, zigzag microfluidics demonstrates superior separation and purity efficiency due to the sudden channel cross-section expansion at the corners. Within Z-RISE, particles are aligned in either double-side or single-line focusing positions. The transition of particles from a double-focusing line to a single focusing line introduced a new phenomenon referred to as the plus focusing position. We experimentally demonstrated that Z-RISE could enrich leukocytes and their subtypes from diluted and RBC lysed blood while depleting dead cells, debris, and RBCs. Z-RISE was also shown to yield outstanding particle or cell concentration with a concentration efficiency of more than 99.99%. Our data support the great potential of Z-RISE for applications that involve particle and cell manipulations and pave the way for commercialization perspective in the near future.