Wind resistance optimization is crucial for enhancing the rotational speed of supergravity centrifuges. We conducted a study using computational fluid dynamics on the Centrifugal Hypergravity and Interdisciplinary Experiment Facility (CHIEF) under construction at Zhejiang University and validated it experimentally using a ZJU400gt centrifuge. Our findings indicate significant reductions in wind resistance through structural modifications of the CHIEF. Reducing the outer radius from 4650 to 4150 mm decreased wind resistance by 16%, primarily due to reduced effective viscosity in the wake region’s gases. More substantial reductions were achieved by lowering the height of the outer wall from 2200 to 1400 mm, which cut wind resistance by 25%. This height reduction suppressed vortex shedding and Kármán vortex street development via the Venturi effect. Adjustments to the roughness height of wall surfaces further decreased wind resistance, with minimal impact from arm roughness. A critical roughness height was identified, below which no further reductions in wind resistance could be attained. Notably, using disc-shaped arms reduced wind resistance by approximately 73% because of their minimal pressure–resistance components and predominant frictional resistance, highlighting their potential in future high-speed centrifuge designs.