In the post-pandemic context, data-driven design interventions that can endow architectural spaces with mixed-use and open characteristics that are adaptable and environmentally resilient are increasingly important. Ubiquitous semi-public architecture, such as hotel buildings, plays a crucial role in public health emergencies. Many hotels adopt mixed-use and open room spatial layouts, integrating diverse daily functions into a single tiny space, fostering flexible utilization and micro-scale space sharing; however, these also introduce potential health risks. This study offers a comprehensive evaluation of the indoor environmental quality (IEQ) of a hotel room space and discusses feasible intervention strategies for healthier renovation and rehabilitation. Taking a hotel in Shenzhen as a case, a multi-domain environmental assessment was conducted during the COVID-19 quarantine period in the summer of 2022. The study examines the health risks inherent in the hotel’s guest room and the varying patterns of IEQ factors across the hotel’s domains, including volatile organic compound concentrations, physical environmental parameters, and heat stress indices. The results illustrate diverse change trends in the chemical, physical, and heat stress factors present in the tested quarantined hotel room space throughout a typical summer day. Although most of the examined environmental factors meet local and global standards, some problems draw attention. In particular, the PM2.5 concentration was generally observed to be above the World Health Organization (WHO) air quality guideline (AQG) standards, and the interior lighting did not meet required standards most of the time. Moreover, correlation and multiple regression analyses uncover significant influence by physical environmental conditions on the concentrations of chemical pollutants in the hotel room. The study preliminarily identifies that higher relative humidity could lead to a lower concentration of CO2 while a higher PM2.5 concentration. Wet bulb globe temperature (WBGT) was observed to positively affect CO2 concentration. Further, the results suggest that even with relatively rigorous initial adjustment and re-renovation, multi-domain environmental quality in air-conditioned quarantine hotel rooms should be monitored and ameliorated from time to time. Overall, this study offers a scientific foundation for healthier upgrades of existing hotel buildings as well as provides insights into achieving environmental resilience in newly constructed hotel buildings for the post-pandemic era.