Abstract: To address signal integrity challenges in high-speed cable design, a systematic study on the optimized application of electromagnetic simulation technology and its impact on key transmission parameters was conducted. Precise three-dimensional electromagnetic models were established to analyze the effects of various material and process factors—including conductor surface roughness, coating thickness, shielding material, structural coupling strength, and geometric eccentricity of conductors/inner jackets—on characteristic impedance, insertion loss (S_DD21), and differential-to-common mode loss (S_CD21). Key findings were identified: Conductor surface roughness was found to significantly deteriorate S_CD21; a strong-coupling structure effectively improved S_DD21; horizontal eccentricity in conductors or inner jackets severely compromised signal balance. Through case-study simulations and measurements, simulation errors for both impedance and S_DD21 were found to be below 2.5%, while S_CD21 showed consistent trends between simulation and measurement, though with notable sensitivity to process variations. Electromagnetic simulations were demonstrated to efficiently guide performance optimization and process parameter control in high-speed cable design, significantly enhancing development efficiency and product reliability.