High summer temperatures, intense solar radiation, and restricted ventilation in arid desert regions often cause heat accumulation and spatially non-uniform temperature distributions in greenhouses, constraining sustainable protected agriculture. This study investigated a multi-span plastic greenhouse in Xinjiang, China, using a field-validated three-dimensional computational fluid dynamics (CFD) model. Nine combinations of side- and roof-vent openings were evaluated under sunny and cloudy conditions to compare crop-zone temperature and airflow characteristics. The results showed that side-vent opening primarily controlled outdoor-air inflow, airflow penetration, and crop-zone cooling, whereas roof-vent opening mainly affected upper-level heat removal and airflow continuity. Their performance therefore depended on coordinated opening ratios. Under sunny conditions, high-temperature zones above 45 °C developed near the roof and arch shoulders. Enlarging the side vents and appropriately matching the roof-vent opening effectively reduced heat accumulation. In the integrated crop-zone assessment, S3T3 achieved the lowest mean crop-zone temperature of 37.32 °C, 7.35% lower than that under S1T1. Its temperature standard deviation was σ = 0.012, and its cooling demand index was Y_c = 0.406, approximately 74.5% lower than that of S1T1. Optimizing side- and roof-vent combinations can therefore improve the greenhouse thermal environment without energy-intensive mechanical cooling, providing a basis for energy-efficient operation and sustainable protected crop production in extreme climates.