Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment. Display omitted •High-throughput screening identifies brivanib as a cGAS activity-enhancing compound•Brivanib targets cGAS to boost its activation by enhancing its DNA binding affinity•Brivanib enhances platinum-induced type I IFN responses in tumor cells•Brivanib and cisplatin synergistically control tumors by boosting CD8+ T cell Liu et al. identify brivanib as a cGAS activity-enhancing compound and provide a proof-of-concept for sensitizing platinum-based chemotherapy by boosting cGAS-mediated antitumor immunity. Brivanib may serve as a drug candidate for sensitizing platinum-based chemotherapeutics in cancer treatment and intervention of cGAS-related diseases.