Abstract: Most of the existing ventilation system optimization designs focus on general mine ventilation systems, and there are few optimization designs for regional mine ventilation systems. In order to solve this problem and achieve balanced ventilation of the underground air network, taking the Wudong Coal Mine in Urumqi, Xinjiang as the research object, the stability of the regional ventilation system is analyzed and studied by using ventilation resistance measurement and ventilation network calculation method. The results are showed as follows. ① In Wudong Coal Mine, under the effect of the main ventilator pulling and natural wind pressure variation in the north and south regions, the air volume of +400 m horizontal track roadway is extremely unstable, and there is often less wind or even reverse wind flow. ② The efficiency of the main ventilator is low, the efficiency is 42% in the south region and 38% in the north region. The mine ventilation resistance value corresponding to the working condition point is lower than the resistance value in the high efficiency region. ③ The natural wind pressure of Wudong Coal Mine varies greatly in autumn and winter. The maximum fluctuation of natural wind pressure in the north region is about 65 Pa, which affects the stable operation of the main ventilator in the north region. The optimization design is proposed for the problems of the regional ventilation system of Wudong Coal Mine. It is proposed to construct ventilation facilities such as air walls and dampers at each production level in the north region, increase the ventilation resistance in the north region, and increase the air distribution volume in the south region according to the actual situation of the mine. Moreover, it is suggested to increase the negative pressure of the mine, add air volume adjustment facilities in the +400 m horizontal track main roadway, and strengthen the air volume monitoring of the roadway to avoid excessive air volume. After the implementation of the optimization scheme, the negative pressure in the north region is increased, which is beneficial to resist changes in natural wind pressure. After the resistance increase and adjustment at various levels in the north region, the mine resistance distribution is relatively reasonable and the air flow is relatively stable, which improves the safety and stability of the mine ventilation system. The efficiency of the main ventilator has also been significantly improved. The wind flow direction of the +400 m horizontal track roadway can be kept stable under the effect of the north-south pressure difference, and there is no more problems of less wind or reverse wind flow. The stability of the air volume has also been greatly increased. The air volume and pressure of other main wind locations are not abnormal. The operation stability of the main ventilator is improved, which proves the effectiveness of the optimization scheme.