Abstract: Negative pressure diaphragm pumps achieve fluid transportation through the reciprocating motion of the diaphragm, and are widely used in fields such as precise flow and vacuum control due to their capabilities of deep vacuum extraction and high-pressure fluid compression. The achievable negative pressure level and its stability are critical factors affecting pump performance metrics such as flow rate, noise emission, and load vibration. A structural optimization method for high-negative-pressure diaphragms is proposed based on the principle that reducing the volume displaced by diaphragm deformation can enhance negative pressure performance. The approach involves enlarging the rigid support beam of the diaphragm and reducing the eccentricity of the drive wheel, and its optimization effect is experimentally verified. The experimental results show that compared to the original design, the optimized diaphragm pump exhibits a 4.8% increase in steady-state negative pressure, a 7.0% rise in output flow rate, an 11.1% reduction in operating noise (sound pressure level), and a 34.9% decrease in vibration acceleration at key measurement points. Furthermore, the attenuation of performance indicators after accelerated aging tests was significantly mitigated. The presented structural optimization method effectively directs performance enhancement of diaphragm pumps toward higher negative pressure and lower disturbance, while simultaneously improving product durability and reliability.