Urban areas experience the urban heat island (UHI) effect, which affects the thermal comfort and energy consumption of buildings. These consequences could vary depending on the socio-economic status of the neighbourhoods. Few studies have investigated how UHI affects socio-economically contrasting districts in thermal comfort and energy performance. Therefore, the primary goal of this research is to evaluate and compare the energy efficiency and thermal comfort conditions of residential buildings in the same city (Temuco, Chile) but located in socio-economically contrasting neighbourhoods. Urban weather files were first modelled in four urban zones using UWG software. Also, EnergyPlus building simulations were conducted to evaluate discomfort hours in adaptive comfort models and energy performance. The results showed annual average UHI intensities between 1.5 and 2.5 K. Urban–rural cooling energy load differences ranged between 12.47% and 38.92%, while heating energy load differences ranged between -20.47% and -81.95%. These distinctions depended on the urban zone, residence model analysed, or energy building standard applied. Similarly, urban-rural differences in thermal comfort times varied from 0.5% to 100%. Results illustrate that the risk of overheating could increase in socio-economically vulnerable areas. This issue could worsen if urban segregation continues to generate poor urban design in low-income districts.