Abstract As an endemic species of the Qinghai–Tibet Plateau, the Plateau Pika (Ochotona curzoniae) exhibits adaptation to the extremely high-altitude environment and possesses a number of distinct physiological characteristics. In order to explore potential mechanisms underlying the adaptation of plateau pikas, we investigate transcriptomic differences across tissues (heart, liver, spleen, lung, kidney, muscle, cerebellum, left brain, and right brain) of the Plateau Pika, in a comparative framework. We analyze possible mechanisms of adaptive evolution by including a transcriptome analysis across the 9 tissues from 3 male and 4 female O. curzoniae and contrasting results with the 8 male and 4 female Gansu Pika (O. cansus) that inhabits the lower middle altitudes. Differential expression and protein–protein interaction network analyses were used to identify the differentially expressed genes and their primary functions. By analyzing interspecific differences, we identified significant adaptive transcriptional changes in the heart, lung, and spleen of the Plateau Pika. Specifically, upregulated genes in these tissues not only show a substantial association with apoptosis and DNA damage repair, but also demonstrate apparent enrichment in biological pathways related to energy metabolism and immune regulation. The majority of downregulated genes exhibit decreased activity in metabolic pathways particularly in muscle, spleen, kidney, and brain tissues. We further reveal the pivotal gene interaction networks of the 9 tissues. Our study provides valuable insight into adaptive mechanisms underlying evolution of Plateau Pika at extreme altitudes.