Terahertz (THz) radiation has a wide range of applications including use in medicine. However, effects of high‐power THz radiation have not been clearly elucidated. We used a 2.52 THz self‐made optically pumped gas THz laser, the low‐ and high‐energy group, to irradiate the backs of Hartley guinea pigs. RNA‐sequencing was done to explore global transcriptional responses in the irradiated skin. Gene Ontology analysis revealed that differentially expressed genes (DEGs) between the unexposed and low‐energy exposed groups were associated with skin development, skin barrier establishment, and multicellular organismal water homeostasis or water loss regulation via the skin. On the other hand, comparison between the unexposed and high‐energy exposed groups showed that the DEGs mediated monocarboxylic acid metabolism, blood vessel morphogenesis, establishment of skin barrier, blood vessel development, or angiogenesis. Our analyses demonstrate the potential effects of high‐power THz source on the skin and sets the basis for further studies on the safety and application of the high‐power THz in dermatology.