This study evaluated the separation efficiency and developed a pressure drop model for a multicyclone separator used for natural gas purification. The collection and grade efficiencies of a multicyclone separator with 15 single cyclone separators were evaluated at inlet velocities of 6–24 m/s and particle concentrations of 30–2000 mg/m3 at atmospheric pressure and room temperature. The experimental results show that although the collection efficiency of a multicyclone separator was 2%–10% less than that of a single cyclone separator at the same operating conditions, most of the particles larger than 10 μm in diameter can be removed by the multicyclone separator. Based on the theoretical pressure drop models of single and multicyclone separators at atmospheric pressure and the pressure drop data measured on site, a pressure drop model was developed that can be used to predict and calculate the pressure drops of multicyclone separators at different pressures and temperatures during natural gas transportation. The modeling results show that 80–90% of the overall pressure drop of a multicyclone separator can be attributed to the single cyclone separators in it. The pressure drop model proposed in this work can accurately predict the pressure drop for different high-pressure multicyclone separators.