Natural gas separation, particularly the removal of CO2 from CH4, is critical for industrial applications to enhance methane purity, prevent pipeline corrosion, and meet processing and transport specifications. Industrial natural gas separation typically operates at high pressures to enhance separation efficiency and meet processing requirements. Metal-organic frameworks (MOFs), with their tunable pore structures, are promising candidates for this task. In this study, we investigate the high-efficiency separation of natural gas, specifically CO2/CH4, at high pressures using CALF-20, a zinc-based metal-organic framework. The CO2 uptake (4.76 mmol/g, 17.31 wt%) is significantly higher than that of CH4 (2.33 mmol/g, 3.6 wt%), resulting in a high IAST selectivity of 394.57 at 298 K and 25 bar. The dynamic breakthrough experiment further confirmed the excellent separation performance for natural gas. For CO2/CH4 mixtures, the breakthrough experiments revealed CO2 uptakes of 2.36 mmol g-1 for the 1:1 feed and 2.44 mmol g-1 for the 2:8 feed, highlighting the material’s strong and selective CO2 adsorption performance.