Aim The goal of this study was to increase knowledge about the antimicrobial activity of some synthetic Riparin‐derived compounds, alone or in combination with fluoroquinolone antibiotics, against a strain of Staphylococcus aureus resistant to fluoroquinolone by way of overexpression of the NorA efflux pump. Methods and Results Microdilution tests showed that Riparins A and B did not show any significant antibacterial activity against Staph. aureus strains. On the other hand, the intrinsic antibacterial activity increased with increasing lipophilicity of the compounds, in the following order: Riparin‐D (MIC 256 μg ml−1; Log P 2·95) < Riparin‐C (MIC 102 μg ml−1; Log P 3·22) < Riparin‐E (MIC 16 μg ml−1; Log P 3·57). The addition of all riparins to growth media at subinhibitory concentrations caused an increase in the antibacterial activity of antibiotics against the NorA‐overexpressing test strain. Riparin‐B, which has two methoxyl groups at the phenethyl moiety, showed the best modulatory effect. Conclusions Riparin‐E is a good anti‐staphylococci agent, while Riparin‐B functions as a NorA efflux pump inhibitor. Significance and Impact of the Study Our data suggest the possibility of using Riparin‐B in combination with norfloxacin or ciprofloxacin for therapy of infections caused by multi‐drug resistant Staph. aureus.