This study presents a digital microfluidic (DMF) system for drug screening using primary tumor cells, aiming to advance precision medicine in cancer treatment. The system is designed to handle limited tumor cell samples, such as those from early-stage cancer patients, and to provide rapid, high-throughput drug screening. The DMF chip is integrated into a portable device with a user-friendly control panel, allowing for on-site drug screening and immediate results. The system's smart electrode-sharing logic increases throughput and reduces footprint, enabling parallel screening of three drugs on a 4 × 4 cm² chip. The effectiveness of the DMF system was validated in an MDA-MB-231 breast cancer xenograft mouse model and clinical liver cancer specimens. In the mouse model, drugs screened on-chip showed consistent tumor suppression in mice treated with effective drugs, while those ineffective on-chip exhibited similar results to controls. In the clinical samples, the identified effective drugs were consistent with the absence of mutations in their related genes, as determined by exome sequencing. The study also explored combinatorial drug screening and the presence of cancer stem cells in clinical samples. The results demonstrated the reliability of the DMF platform for on-chip drug screening, guiding in-vivo cancer therapy. The system's advantages include its small footprint, high throughput, and cost-effectiveness, making it a promising tool for precision medicine in cancer treatment. However, limitations such as the need for manual control and the potential for unexpected mutations in primary tumor cells were noted, and future work will focus on improving these aspects.This study presents a digital microfluidic (DMF) system for drug screening using primary tumor cells, aiming to advance precision medicine in cancer treatment. The system is designed to handle limited tumor cell samples, such as those from early-stage cancer patients, and to provide rapid, high-throughput drug screening. The DMF chip is integrated into a portable device with a user-friendly control panel, allowing for on-site drug screening and immediate results. The system's smart electrode-sharing logic increases throughput and reduces footprint, enabling parallel screening of three drugs on a 4 × 4 cm² chip. The effectiveness of the DMF system was validated in an MDA-MB-231 breast cancer xenograft mouse model and clinical liver cancer specimens. In the mouse model, drugs screened on-chip showed consistent tumor suppression in mice treated with effective drugs, while those ineffective on-chip exhibited similar results to controls. In the clinical samples, the identified effective drugs were consistent with the absence of mutations in their related genes, as determined by exome sequencing. The study also explored combinatorial drug screening and the presence of cancer stem cells in clinical samples. The results demonstrated the reliability of the DMF platform for on-chip drug screening, guiding in-vivo cancer therapy. The system's advantages include its small footprint, high throughput, and cost-effectiveness, making it a promising tool for precision medicine in cancer treatment. However, limitations such as the need for manual control and the potential for unexpected mutations in primary tumor cells were noted, and future work will focus on improving these aspects.