Stressors are especially widespread in urban agglomerations. Common themes of built environment interventions that support health and well-being are blue and green infrastructure, indoor and outdoor air quality, thermal comfort, access to natural lighting, and acoustics. Given the current megatrends of increasing summer temperatures and the high popularity of home offices, we aimed at modeling thermal comfort changes of people working at home in three Austrian cities (Vienna, Innsbruck, and Graz) during the next decades until 2090. We present findings based on (I) an inter-disciplinary literature search and (II) indoor and outdoor climate simulations for actual and future climate scenarios. Based on the results, we discuss the potential impacts for work and human health and well-being, and we suggest a framework for the home office in “post-COVID-19 Austria” that integrates social, ecological, and economic aspects. The results of our study indicate that, in future climate scenarios, overheating of the interior can no longer be prevented without active cooling measures and nature-based solutions. Recommendations on the adjustment of behavior under climate change, including greening, adequate ventilation, and cooling techniques, are thus urgently needed for employees who are working from home in order to maintain physical and mental health and wellbeing.