Ventilation and soil moisture influence greenhouse cultivation. Experiments were conducted at Xinxiang Irrigation Research Base of the Chinese Academy of Agricultural Sciences, Henan Province, China, to identify how ventilation and irrigation affected the greenhouse microenvironment. To develop ventilation and irrigation protocols that increase crop yield and improve the quality of drip-irrigated tomatoes grown in the greenhouse, three ventilation modes (T1, T2, and T3) were developed by opening vents in different locations in a completely randomized pattern. T1 had open vents on the north wall and roof of the greenhouse. T2 had open vents on the north and south walls and the roof. T3 had open vents on the north and south walls. Three irrigation treatments (W1, W2, and W3) were designed based on the accumulated water surface evaporation (Ep) of a standard 20-cm evaporation pan. The irrigation quantities were 0.9×Ep (W1), 0.7×Ep (W2), and 0.5×Ep (W3). The spatial and temporal distributions of temperature and humidity were analyzed for different combinations of ventilation and irrigation to identify their effects on tomato yield and fruit quality. Major results were as follows: 1) In addition to solar radiation, ventilation had an important influence on Ep and, on a daily scale, ventilation had a significant effect on Ep (P < 0.05). 2) Ventilation had a significant effect on indoor wind speed, but the effect varied during different growth stages. During the flowering and fruit setting stage, wind speed for T2 significantly differed from those of T1 and T3 (P < 0.01). During the harvest stage, the three ventilation treatments had significantly different effects (P < 0.01). A correlation analysis showed high correlation between T2 wind speed and T3 wind speed (R = 0.831), but low correlation between T2 wind speed and T1 wind speed (R = 0.467). 3) The effect of ventilation on greenhouse humidity and temperature was greater than the effect of irrigation. The differences in air temperature among various combined treatments of ventilation and irrigation were significant for the flowering and fruiting stages (P < 0.05), but they were not significant for the late harvest stage (P > 0.05). There were significant differences in humidity on sunny days (P < 0.01), but no significant differences on cloudy or rainy days (P > 0.05). Air temperature at 2 m was greater than canopy temperature, but humidity at 2 m was less than that at canopy level. 4) Irrigation water quantity was positively correlated with tomato yield and negatively correlated with the fruit quality indicators total soluble solids, vitamin C content, organic acid content, and soluble sugars content. Ventilation had an effect primarily during the harvest period; it had no significant effect on yield (P > 0.05). However, it had a significant effect on vitamin C content and the sugar:acid ratio (P < 0.01). The combination treatment of T2W2 is recommended as the optimal treatment for greenhouse tomatoes using drip irrigation to produce an optimal combination of crop yield and fruit quality. This study provides theoretical and technical support for the improvement of greenhouse climate control by optimizing greenhouse ventilation and irrigation techniques to promote tomato yield and improve fruit quality.