Many chemotherapeutic drugs induce oxidative stress by accelerating the accumulation of reactive oxygen species (ROS), which triggers the death of cancer cells and then causes severe DNA damage in cancer cells. Here, we proposed using a preclinical microfluidic model to evaluate the combination of doxorubicin and aspirin (DA) for anti-inflammatory therapy using patient-derived circulating tumor cell (CTC) clusters. The preclinical model could perform high-throughput screening of drug combinations and used valves to regulate media inflow for CTC cluster formation. We demonstrated that low-dose aspirin (445–500 mg/ml) and a suboptimal dose of doxorubicin (0.5 D) for seven days could produce higher killing efficacy and significantly reduced the proportion of cancer stem cells and colony-forming ability. Compared with the treatment with doxorubicin alone, the intracellular oxidative activity in the sample under combinatorial DA treatment was reduced, as demonstrated by the intensity of Calcein AM. We demonstrated that the treatment outcomes were mediated by the reduction of COX-2, which was associated with inflammation triggered by ROS. Overall, the preclinical model could be used as a proof of concept to demonstrate the efficacy of anti-inflammatory combinatorial therapies by influencing oxidative stress. Similar research could provide a basis for more DNA-related cancer treatment research in the future.