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Background: Treatment of device-related infections by drug-resistant <i>Staphylococcus aureus</i> can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin–rifampin and ciprofloxacin–rifampin combinations in killing methicillin-resistant <i>S. aureus</i> (MRSA) using a time–kill assay. Methods: We randomly selected 15 vancomycin-susceptible <i>S. aureus</i> (VSSA) strains, 3 vancomycin-intermediate <i>S. aureus</i> (VISA) strains, and 12 heterogeneous VISA (hVISA) strains from the Asian Bacterial Bank. Time–kill experiments were performed in duplicate for each isolate. Viable bacterial counts were determined at 0 h, 4 h, 8 h, and 24 h for the ciprofloxacin– and levofloxacin–rifampin combinations at 1× MIC and 0.5× MIC. We compared synergistic and antagonistic interactions between the two combinations. Results: The viable bacterial count significantly decreased after 24 h of exposure to ciprofloxacin–rifampin and levofloxacin–rifampin combinations, with synergy observed more frequently in isolates exposed to ciprofloxacin–rifampin (43.3%) than levofloxacin–rifampin (20.0%) (<i>p</i> = 0.0082). The synergistic interactions of both combinations were more frequently observed in resistant strains with high MICs of ciprofloxacin (≥16 mg/L) and levofloxacin (≥8 mg/L). Levofloxacin tended to exhibit more frequent antagonistic interactions with rifampin than ciprofloxacin, although there was no statistical difference in antagonism between the two combinations. Conclusions: Our study demonstrated that ciprofloxacin exhibits superior synergistic activity against MRSA strains, including VISA/hVISA, when combined with rifampin compared with levofloxacin. High MICs of fluoroquinolones were found to predict synergism. Our results suggest that ciprofloxacin may be a more effective choice than levofloxacin for combination therapy with rifampin in the treatment of MRSA infections.