Serpentine micromixers are simple in design, have a high mixing performance, and thus are preferable among passive micromixers. Conventional geometries such as square-wave, circular, and zigzag have widely been investigated by researchers. High pressure loss is the main challenge which diminishes its cost effectiveness. To mitigate the pressure loss and maintain high mixing efficiency, a novel 3D square-wave serpentine micromixer with misaligned inflow is introduced. The design integrates the concept of non-aligned inlets and highly effective square-wave cross-section inside a serpentine micromixer. Flow analysis was done for Reynolds number 5 to 50 and a mixing efficiency above 90% was achieved. The design amalgamates two square-waves cross sections with lateral misalignments thereby producing a vortex flow at each mixing junction (chamber). The results suggest strong vortex mixing along with crossflow phenomenon (vortex propagation and intensification) inside the mixing chamber. The core vortex region was also analyzed. For Reynolds number 30, mixing index of 0.92 is observed with pressure loss around 5 kPa and mixing length 3.7 mm. A detailed comparative study is also established, which successfully demonstrates the edge of proposed design.