Heat-related mortality remains health challenges exacerbated by climate change, with sex-based differences in outcomes, yet underlying mechanisms remain poorly understood. This study examined transcriptomic responses to heat exposure in peripheral blood mononuclear cells from 19 heat stroke patients (8 males, mean age 64.8 ± 6.6 years
11 females, mean age 49.7 ± 11 years) and 19 controls (11 males, mean age 48.9 ± 9.6 years
8 females, mean age 44.9 ± 11.8 years). At admission, gene expression revealed upregulation of heat shock protein genes and pathway analysis, demonstrated activation of heat shock and unfolded protein responses across both sexes consistent with proteotoxic stress. However, distinct metabolic, oxidative stress, cell cycle control and immune responses were observed within each sex. Females displayed inhibition of protein synthesis, oxidative phosphorylation, and metabolic pathways, including glucose metabolism, indicative of a hypometabolic state. Males maintained metabolic activity pre-cooling, and enhanced ATP production post-cooling. Females activated NRF2-mediated oxidative stress responses and inhibited DNA replication and mitosis, potentially mitigating genomic instability, while these pathways showed limited regulation in males. Females promoted innate immunity via IL-6, inflammasome, and TREM1 signaling, whereas, males showed suppression of both innate and adaptive immunity, including IL-12, Th1, and T-cell receptor pathways. Upstream analysis identified over 100 transcription factors in both sexes. Males primarily relied on transcriptional mechanisms, whereas females also exhibited translational regulation via LARP1, FMR1, IGF2BP1, and EIF6. These findings suggest distinct, sex-specific molecular adaptations to heat stroke, underscoring the need for targeted therapeutic strategies to mitigate heat-induced morbidity and mortality.