In order to obtain antibacterial candidate compounds, using the principle of pharmacodynamic fragment combination, the thiazole fragment was introduced into the structure of the seedling compound osthole. Twenty-six osthole derivatives were designed and synthesized, and confirmed by ¹H NMR, ¹³C NMR and elemental analysis. The antibacterial activities against S. aureus, E. coli, methicillin-resistant S. aureus (MRSA) and fluoroquinolone-resistant E. coli (FREC) were evaluated. The results showed that the minimum inhibitory concentrations (MICs) of N-(4-(2-fluorophenyl)thiazol-2-yl)-2-((8-(3-methyl- but-2-en-1-yl)-2-oxo-2H-chromen-7-yl)oxy)acetamide (5g) were 2, 4, 2, 4 μg/mL, respectively. The MICs of N-(4-cyclo- propylthiazol-2-yl)-2-((8-(3-methylbut-2-en-1-yl)-2-oxo-2H-chromen-7-yl)oxy)acetamide (5w) were 2, 2, 4, 4 μg/mL, respectively. The MICs of N-([2,4'-bithiazol]-2'-yl)-2-((8-(3-methylbut-2-en-1-yl)-2-oxo-2H-chromen-7-yl)oxy)acetamide (5x) were 1, 2, 2, 2 μg/mL. respectively. Their anti-S. aureu activities were comparable to the control drug oxacillin and superior to norfloxacin, and anti-E. coli, MRSA, and FREC were superior to the control drugs oxacillin and norfloxacin. The connection of thiazole fragment to the structure of osthole can effectively enhance antibacterial activities.