This study investigated the inhibitory effects of high salt concentrations on the biological reduction of perchlorate and identified the optimal reactor configuration for effective treatment. In wastewater containing equivalent concentrations of NaCl, NH4Cl, HCl, and H2SO4, perchlorate reduction rates were comparable. However, as the conductivity of NaCl increased from 8,000 μS/cm to 24,000 μS/cm, a marked decline in the biological reduction rate of perchlorate was observed. No reduction occurred at conductivities above 32,000 μS/cm, indicating that salinity is a significant inhibitory factor in perchlorate biodegradation. Furthermore, the treatment performance of a continuous stirred tank reactor (CSTR) and a plug-flow reactor (PFR) was compared in terms of their ability to meet perchlorate effluent standards. The CSTR achieved a minimum effluent concentration of 2.1 mg/L, which exceeded the effluent standard, whereas the PFR achieved a minimum concentration of 0.001 mg/L, thereby complying with the U.S. EPA effluent standard. The optimal operational parameters for the PFR were identified as a hydraulic retention time of 12 h, a MLSS concentration of 3500–3800 mg/L, and a dissolved oxygen concentration of 0.2–0.5 mg/L. This study provides insights into salinity inhibition thresholds, practical operational parameters, and the comparative performance of reactor configurations for perchlorate removal.