The vacuum-blowing cleaning system, utilizing positive and negative pressure mixed-delivery theory, has been adopted for the road sweeper vehicle. To enhance the solid particle separation performance and to evaluate the motion characteristics of inhaled particles under different structural parameters, the gas-solid flow in the vacuum-blowing cleaning system was investigated by using computational fluid dynamics (CFD) technology. The influence of the main structural parameters on the grade dust collection efficiency and average detention time of the inhaled particles was determined, such as suction-inlet diameter, suction-inlet inclination angle, and front baffle inclination angle. And the interplay between them was also investigated. In addition, a dust collection efficiency model was built, based on uniform design (UD) and multiple regression analysis (MRA), and subsequently verified via experiments. The results revealed that the structural parameters have significant influence on the dust collection performance. The suction-inlet diameter, front baffle inclination angle, and suction-inlet inclination angle exerted the highest, second-highest, and lowest influence, respectively. Furthermore, the interaction among structural parameters also influenced the collection performance. The highest, second-highest, and lowest levels of influence were determined for the inlet diameter/baffle inclination angle, inlet inclination angle/baffle inclination angle, and inlet diameter/inlet inclination interactions, respectively. The highest dust collection efficiency (i.e., 96.10%) and a short average detention time of particles in the chamber were realized under the following conditions: suction-inlet diameter and inclination angle: 200 mm and 110°, respectively, and front baffle inclination angle: 105°.