Ventilation challenges induced by extremely low temperatures and complex tunnel structures are presented in ultra-large underground cavern projects in cold regions. Optimized hybrid ventilation layout schemes are investigated to improve ventilation efficiency and guarantee operational safety. A three-dimensional numerical model of the meandering construction tunnel was established. The reliability of the numerical model was validated through field measurements. The influences of three critical factors on working face airflow field stability and CO pollutant removal efficiency were systematically analyzed. The three factors include supply/extraction air volume distribution, extraction duct placement, and overlap distance between supply and extraction ducts. Objective weights of two evaluation metrics were determined by the entropy weighting method. The two metrics are the time for wind speed standard deviation reduction and the time for CO concentration to drop to the safe limit. Multi-objective comprehensive evaluation of 12 ventilation scenarios was conducted via grey relational analysis. Weights of 0.538 and 0.462 are assigned to wind speed uniformity and pollutant removal efficiency, respectively. Both metrics are proved to exert significant impacts on ventilation performance. Scenario 5 is identified as the optimal ventilation scheme. A “left supply, right extraction” layout is adopted in the optimal scheme. A supply/extraction airflow ratio of 1.2 is set in this scheme. Ventilation ducts are arranged along the top of both tunnel sides. Stable airflow distribution is guaranteed by this optimal scheme. Efficient and rapid CO removal is achieved by the scheme simultaneously. Theoretical foundations and practical guidance are provided for ventilation design of complex underground engineering projects in cold regions.