The high-precision and high-purity isolation of circulating tumor cells (CTCs) from whole blood is vital to early cancer detection. Cascaded microfluidic separation is highly efficient because it connects multiple-stage separations in series. Here, we numerically investigated sheathless tumor cell separation with size-dependent cascaded inertial and deterministic lateral displacement (DLD) microfluidic device. The inertial microfluidic is arranged in the first-stage unit for particle focusing and rough sorting, and the cascaded DLD microfluidic is arranged in the second stage for realizing further sorting and purification. A parametric study with flow rate range from 100-600 μl/min and aspect ratio range from 60:100 to 60:300 of the first stage was carried out to optimize channel structure for realizing high-efficiency separation. Then, the pre-separation mechanism within the spiral microchannel was analyzed. The purity of the obtained CTCs and the separation efficiency were further improved using a droplet-type microcolumn DLD microfluidic device as the second unit. The cascade eliminates the need for additional force fields and reduces device complexity while simplifying operation and reducing the chance of sample contamination.