Multistage supercharging is an effective way to solve the problems of low volumetric efficiency and combustion deterioration of piston engines under high altitude conditions. As a critical component of the supercharger system, the high-altitude intercooler performance is challenged to meet the heavy heat load caused by the large boosting ratio. The purpose of this study was to add more knowledge on the high-altitude intercooler performance to the limited existing studies. The intercooler experimental tests were conducted in a high-altitude simulation system, allowing for simultaneous pressure and temperature reductions. A 3D computational fluid dynamics (CFD) model was developed and validated against experimental results to investigate the intercooler performance, including the heat exchange and pressure drop characteristics. The results indicated that the atmospheric conditions and cruising speed significantly affected the intercooler performance. For example, the weighting of the effects of the temperature difference and air density on heat exchange performance varied with altitude. The altitude of 11 km was the turning point of the heat transfer rate because it is the junction of the troposphere and stratosphere. Based on this finding, this study further investigated whether a higher cruise speed could compensate for heat transfer deterioration with increasing altitude, more consistent with actual flight conditions. The simulation results showed that the variation of cruise speed directly affected the effectiveness of the heat exchanger, resulting in a different trend with altitude. Furthermore, the heat exchange of the intercooler fluctuated less with altitude under variable speed conditions. Overall, these findings support more fundamental research on high-altitude intercoolers, which may benefit the design and optimization of high-altitude engines and turbocharged systems.