Anthropogenic climate change has amplified human thermal discomfort in urban environments. Despite the considerable risks posed to public health, there is a lack of comprehensive research, evaluating the spatiotemporal changes in human thermal discomfort and its characteristics in hot-hyper arid regions, such as the Arabian Peninsula (AP). The current study analyzes spatiotemporal changes in human thermal discomfort categories and their characteristics in AP, using the newly developed high-resolution gridded ERA5-HEAT (Human thErmAl comforT) dataset for the period 1979–2022. In addition, the study assesses the interplay between the Universal Thermal Climate Index (UTCI) and El Niño-Southern Oscillation (ENSO) indices for the study period. The results reveal a significant increase in human thermal discomfort and its characteristics, with higher spatial variability in the AP region. The major urban centers in the southwestern, central, and southeastern parts of AP have experienced significant increases in human thermal discomfort (0.4–0.8 °C), with higher frequency and intensity of thermal stress during the study period. The temporal distribution demonstrates a linear increase in UTCI indices and their frequencies and intensities, particularly from 1998 onward, signifying a transition towards a hotter climate characterized by frequent, intense, and prolonged heat stress conditions. Moreover, the UTCI and ENSO indices exhibit a dipole pattern of correlation with a positive (negative) pattern in the southwestern (eastern parts) of AP. The study’s findings suggest that policymakers and urban planners need to prioritize public health and well-being in AP’s urban areas, especially for vulnerable groups, by implementing climate change adaptation and mitigation strategies, and carefully designing future cities to mitigate the effects of heat stress.