Given the close association between inflammation and cancer, combining anti-inflammation therapy is prominent to improve the anticancer effect. Based on I-1, a series of agents targeting COX-2 and Topo I were designed by combining fenamates and phenols. The optimal compound 1H-30 displayed an enhanced inhibitory effect on COX-2 compared to tolfenamic acid and I-1 and showed better inhibition of Topo I than I-1. Importantly, 1H-30 showed potential anticancer effects and suppressed the activation of the NF-κB pathway in cancer cells. 1H-30 inhibited the nuclear translocation of NF-κB and suppressed the production of NO, COX-2, and IL-1β in RAW264.7. In vivo, 1H-30 showed acceptable pharmacokinetic parameters, decreased the tumor growth without affecting the body weight, down-regulated COX-2 and MMP-9, and induced apoptosis in the CT26.WT tumor-bearing mice. Accordingly, 1H-30 as a potential Topo I/COX-2 inhibitor which possessed anti-inflammatory and anticancer effects, with inhibition of the NF-κB pathway, is promising for gastrointestinal cancer therapy.