The increasing demand for agricultural products and scarcity of resources, such as soil fertility, irrigation water, and moderate climate, have driven increased use of indoor vertical farming systems. In this paper, a three-dimensional numerical model is developed to optimize air flow and heat transfer within an indoor system considering transpiration, carbon-dioxide consumption, and oxygen production. The near-wall RNG k−ε turbulent model is implemented to consider the impacts of turbulence and obstacles in the computational domain. To assess the degree of uniformity affecting each tray, an objective uniformity parameter is developed based on the deviation of flow velocity over cultivation trays with respect to the optimal flow velocity. Further, an efficiency parameter is defined based on relative humidity, temperature, and pressure drop to holistically compare the effectiveness of flow inlet and outlet locations. Accordingly, eight designs are studied extensively and one case is found to be the most efficient with an objective uniformity of 91.7% due to high degree of spiral flow circulation. Most importantly, the results suggest that some cases even with low mass flow rates are capable of providing uniform flow distribution, which can significantly reduce energy consumption of indoor vertical farming systems. This newly developed model is proven to be an effective tool for investigating the heat transfer rate and fluid flow uniformity and optimizing cultivation environment for an indoor vertical farming system.