Crete Island is located in the southmost border of East Mediterranean basin, facing exacerbating atmospheric conditions (mainly concentrations of particulates) due to Saharan dust outbreaks. It is worth to note that these episodes are more frequent during spring and autumn, when mild biometeorological conditions become intolerable due to the synergy of the so called Fohn winds. Cretan mountains, especially Psiloritis Mt. (summit at 2456 m), are orientated perpendicularly to the southwest air mass flow, generating the Fohn winds. Propagating from the leeward of the mountains, these dry, hot winds have an effect on prevailing biometeorological conditions. While descending to the lowlands on the leeward side of the range, the wind becomes strong, gusty, and desiccating. This wind often lasts less than an hour to several days, with gradual weakening after the first or the second day. Sometimes, it stops very abruptly. In this work, the authors examined and analyzed the abrupt changes of human thermal perception within specific case studies during which Fohn winds appeared in Heraklion city at the leeward of Psiloritis Mt, associated with extreme Saharan dust episodes, observed within the period 2006–2010. In order to verify the development of Fohn winds, Meteorological Terminal Aviation Routine Weather Reports (METARs, meteorological observations every half hour), were acquired from the Heraklion meteorological station installed by the Hellenic National Meteorological Service (HNMS). The biometeorological conditions analyzed are based on human thermal bioclimatic indices such as the Physiologically equivalent temperature (PET) and the Universal Thermal Climate Index (UTCI). METAR recordings of meteorological variables, such as air temperature, vapor pressure, wind speed, and cloudiness, were used as input variables in modeling the aforementioned thermal indices, so that to interpret the grade of the thermo-physiological stress. The PET and UTCI analysis was performed by the use of the radiation and bioclimate model, “RayMan,” which is well-suited to calculate radiation fluxes and human biometeorological indices. The results of the performed analysis showed even an increase of air temperature from 20 to 30 °C within 5 h, associated with a decrease in the vapor pressure from 11.5 to 9.3 hPa. In addition, the wind speed at 10 m increased from 5.1 to 20.1 m/s, 3.7 to 14.3 m/s with respect to 1.1 m height, during the events of Fohn winds. The biometeorological analysis has given evidence that slight/moderate heat stress classes of the examined thermal indices appear during Saharan dust episodes. Such conditions are uncommon at the beginning of spring season, indicating that Saharan dust episodes are not only responsible for acute health impacts but also for adverse biometeorological conditions, due to the very likely development of Fohn winds towards the wider area of Heraklion, a coastal city in the eastern Mediterranean.