Rupestonic acid is the main active compound in Artemisia rupestris L, which mainly grows in Xinjiang of China. To find its active group, a series of novel rupestonic acid 3-carbonyl analogues were prepared. The structures of the compounds were confirmed by spectral and high resolution mass spectrum. All compounds were evaluated for antiviral activity against influenza A (H3N2 and H1N1) and B viruses in MDCK cell cultures. The compounds displayed a confined structure-activity relationship. Compound 13 with allyl group was the most potent inhibitor against influenza A/H1N1 virus with an IC50 value of 4.27 μM and a SI value of 27.04. Dihydrogen amide 3 possesses the good potency against influenza B virus with an IC50 value of 5.5 μM and a SI value of 13.