Multidrug-resistant Staphylococcus aureus (S. aureus) were taken as object to investigate the reversal effect of sertraline on multi-drug resistance of S. aureus and its reversal mechanism through the determination of minimum inhibitory concentration，growth rate，time-kill curves under the combination of non-antibiotics sertraline and different antibiotics，as well as transcriptional level of the drug resistance gene mecA and the efflux pump gene norA by real-time PCR． The results indicate that when the sertraline concentration is higher than 1 μg/mL，the growths of S. aureus are inhibited; when sertraline (1/2 MIC) is combined with tetracycline，it has a bactericidal effect on S. aureus． Sertraline combined with tetracycline，ciprofloxacin，and clindamycin，it has synergistic or additive inhibitory effect on S. aureus，which could increase the sensitivity of three antibiotics by more than 75%． Low concentration of sertraline could significantly reduce the expression of the efflux pump gene norA and mecA gene in SCCmec gene cassettes of S. aureus． The results show that sertraline can regulate the multi-drug resistance of S. aureus by inhibiting the expression of resistance genes such as norA and mecA，and reverse the resistance of S. aureus to various antibiotics when it is combined with antibiotics．