<p>Cancer remains the leading cause of death worldwide, and early detection can significantly reduce patient mortality. Circulating tumor cells (CTCs), which are tumor cells shed from the primary tumor and transported to distant sites through the bloodstream, are key biomarkers for cancer diagnosis and contain critical information reflecting the primary tumor, making them important for monitoring cancer progression. Microfluidic chips utilizing a purely physical capture technique based on the size and deformability differences between CTCs and other blood cells have proven to be effective in capturing CTCs. This study investigates three high-gradient microstructured hybrid microfluidic chips (HGMH-Chips), each incorporating a microarray structure and a distinct geometric gradient design: linear, sawtooth, and waveform. Multiphysics simulations revealed significant differences in pressure distribution among the chip configurations. Notably, the sawtooth design exhibited a more uniform pressure drop, with only 25% of the particles in the high-pressure region. We employed two cancer cell lines (MDA-MB-231 and A549) to evaluate the chip’s capture capability. Additionally, we compared the capture efficiency and cell viability across the three designs in a single cancer cell system. Experimental results demonstrated that the sawtooth chip achieved a capture efficiency of up to 70%. When applied to mixed samples containing leukocytes, the high-gradient design exhibited a capture purity of up to 98%, effectively isolating a small number of cancer cells from complex samples. This model holds promise for the capture of CTCs in complex systems. Furthermore, the microarray structure aids in stabilizing the captured cancer cells, enhancing separation efficiency. This study presents a novel chip structure design for tumor cell capture, which holds promise for improving the capture of tumor cells in complex biological samples.</p> Graphical Abstract <p></p>