One of people’s greatest concerns about air quality degradation is its impact on human health. This work is a case study that aims to investigate the air quality and the related impact on people’s health in a coastal city over the eastern Mediterranean. The analysis proceeded during a low-tourist density period, covering the days from 17 to 27 November 2022. Hourly PM2.5, NO2 and O3 concentration records from three, mobile, Air Quality Monitoring Systems (AQMS), established in an urban location, port and central area of Rhodes city, are analyzed. To investigate the impact of pollution levels on human health, the Air Quality Health Index (AQHI) is calculated. The daily and diurnal variation of pollutants’ concentration and AQHI among the different areas, as well as the relation among the ambient air pollutants and AQHI, are studied. Additionally, to investigate the impact of wind regime on the variation of pollution and AQHI levels, the hourly zonal and meridional wind-speed components, as well as the temperature at 2 m, the dew point temperature at 2 m, and the height of the boundary layer from ERA5 reanalysis, are retrieved for the region of the southeastern Mediterranean. Results show that the highest pollution level occurs in the city center of Rhodes, compared to the rest of the studied locations. In general, the findings do not show exceedances of the pollutants’ concentration according to the European Directive 2008/50/EC. Moreover, findings show that in some cases, the health risk is classified from Low to Moderate in terms of AQHI. The analysis indicates that the climate conditions affect the pollutants’ concentration due to dispersion, and likely, the atmospheric transport of pollutants. Finally, this work aims to improve the knowledge regarding the air quality of southeastern Greece, promoting the framework for the green and sustainable development of the South Aegean Sea.