This paper presents a simple and effective control solution to regulate temperature and humidity inside a greenhouse, which are the main climatic variables affecting crop growth and health. A multivariable control strategy with inverted decoupling is proposed in two schemes. The nighttime control scheme uses heating and dehumidification, and the daytime control scheme uses natural ventilation, dehumidification, and humidification. A system identification methodology is used to obtain low-order linear models from data measured in a greenhouse. This simplifies the design of proportional–integral (PI) controllers and allows the use of well-known control techniques. For instance, anti-windup is used to deal with the saturation of the actuators and for a bumpless transfer mechanism to switch between the nighttime and the daytime control schemes. Setpoint weighting is used for the humidity controllers to attenuate undesired effects on the temperature control loop when the humidity setpoint is changed. Furthermore, split range control is used for the first time to control humidity by combining a heat-pump dehumidifier and a fogging system. The control solution presented in this work allows the integral absolute error to be reduced, on average, by 88.5% for the interactions affecting the temperature control loop, and by 85.6% for the humidity control loop, compared to decentralized PI control. The control schemes have been tested in simulation with real disturbance data from a Mediterranean greenhouse and in preliminary form in a real facility to conclude that the proposed multivariable control strategy could be effective in decoupling the temperature and the humidity control loops.