Among the aspects with major impacts on the energy and environmental performance of a building, the thermal insulation of the opaque elements of its envelope stands out. This work assesses the influence of the application of thermal insulation to the opaque elements of the building’s envelope on the thermal comfort conditions indoors; moreover, the influence of the thermal insulation on the energy, environmental, and economic costs over the building’s complete life cycle is evaluated. For this purpose, the three most commonly used thermal insulating materials (expanded polystyrene—EPS, extruded polystyrene—XPS, and mineral wool—MW), thicknesses between 0 (without insulation) and 40 cm, five climates (hot, warm, moderate, cold, and very cold), and six types of use (apartment, housing, clinic, school, bank branch, and supermarket) were considered. EPS reveals itself to be the most promising thermal insulation material, both in economic and environmental terms, so it was selected for this study. The EPS’ optimal thickness depends on the building’s type of use, the climate, and the perspective from which the assessment is carried out (energy, environmental, or economic). The results show that the economically optimal thicknesses of thermal insulation are significantly lower than the corresponding ones in environmental terms. Furthermore, the application of thermal insulation to the opaque building’s envelope is more beneficial in energy and environmental terms than from an economic perspective.