In order to search for antibacterial compounds, the natural product osthol was used as raw material to prepare intermediate I by selenium dioxide oxidation, and then intermediate II was prepared by sodium chlorite oxidation. Finally, fifteen osthol amide derivatives were prepared by DCC condensation of intermediate II and amine. The structures of compounds were confirmed by 1H NMR, 13C NMR and MS. The results showed that these derivatives had potential antibacterial activities, most of the target compounds had better antibacterial activity than osthol, and some of them had excellent antibacterial activity against methicillin-resistant staphylococcus aureus (MRSA). Among them, compound Ⅲo showed the best anti-MRSA activity with the minimum inhibitory concentration (MIC) of 64 μg/mL, which was much better than that of oxacillin.