Cyclooxygenase and inducible nitric oxide synthase are key proteins in two different pathways that produce inflammation. In this study, we based on the principle of pharmacophore combination to obtain small molecules that can block the dual targets of COXs and iNOS. We screened two pharmacophores with anti-inflammatory activity, chromone ring and sulfonamide from clinical drugs, natural products and other compounds with outstanding biological activity, and synthesized 9 novel chromone-sulfonamide derivatives, among which compounds 4a, 4b, 4c, 4d and 4i exhibited different degrees of COXs and iNOS inhibition. In particular, compound 4i exhibited the most significant dual inhibitory effect, with an IC50 of 28.83 ± 0.06 μM for PGE2 and an IC50 of 36.95 ± 3.9 μM for NO content, which was superior to the positive drugs ibuprofen (IBU, IC50 = 246.5 ± 3.8 μM) and L-canavanine (L-Can., IC50 = 440.0 ± 7.9 μM). In addition, the research group used Discovery Studio to dock the target compounds with COX-1, COX-2 and iNOS, respectively, and the results showed that compound 4i had the best docking method (its -CDOCK INTERACTION ENERGY scores were 48.2967, 45.3519 and 43.4412, respectively, which were better than those of other compounds), which was consistent with the results of activity experiments, and the chromone ring and sulfonamide group could form hydrogen bonds between the two target proteins, conjugation and van der Waals interactions, indicating that the chromone ring and sulfonamide group are key pharmacophores. In addition, a preliminary study of the structure-activity relationship of the compound was carried out to identify the key factors affecting the anti-inflammatory activity, and 4i matched the structure-activity relationship, which indicated that 4i was a lead compound for the development of dual COXs/iNOS inhibition for the treatment of inflammatory diseases.