Despite the acknowledged positive effects of vegetation at urban, neighborhood and building scales, there are still only limited comprehensive design tools for multi-scale evaluation of the microclimate and thermal benefits of plants and building-integrated vegetation (BIV) systems. The paper describes a case study in the city of Palermo (Italy) that applied simulation methodology to quantitatively assess the microclimate effects of different neighborhood and building retrofit scenarios where vegetation plays a main role. The simulation workflow moves from a micro-urban to a building scale assessment by linking the ENVI-met software to the building energy simulation program EnergyPlus. The study takes two complementary directions. Firstly, it analyses the influence of plants on urban microclimates to enhance outdoor and indoor temperatures. Secondly, it assesses the benefits of different technical solutions applied to buildings, including BIV systems and windows substitutions, to further improve their thermal behavior. The results of the simulations show a significant reduction in outdoor and indoor temperatures, questioning traditional urban renovation practices and drawing attention to the importance of multi and inter-scale approaches for high-accuracy investigations into buildings’ thermal performances.