This study assesses the impact of climate change on the energy performance and thermal comfort of typical urban residential buildings in Athens, Greece, considering two different climate scenarios (RCP 4.5 and RCP 8.5). Representative neighborhoods were analyzed, located in two Local Climate Zones (LCZs). Hence, for each LCZ, typical buildings were simulated with the EnergyPlus software, representing archetype multi-family Greek buildings, for three time periods; (i) 1980–2000, (i) 2040–2060 and (iii) 2080–2099. The outcomes of the analysis indicate a consistent decrease in heating demand (up to 37%) and a sharp increase in cooling loads (up to 145%) by the end of the century, especially under RCP 8.5. Indoor thermal comfort, assessed via the Fanger PMV index, worsens significantly, particularly during summer and on upper floors. These findings highlight the urgent need for targeted retrofit policies that will focus on passive cooling strategies in order to address rising energy demands and discomfort risks in vulnerable housing stocks during future summer periods and intensified heat waves. The study also underscores the importance of long-term resilience planning and climate-adaptive retrofit measures for European residential buildings.