High-altitude environments impose intense stresses on living organisms and drive striking phenotypic and genetic adaptations, such as hypoxia resistance, cold tolerance, and increases in metabolic capacity and body mass. As one of the most successful and dominant mammals on the Qinghai-Tibetan Plateau (QHTP), the plateau pika (Ochotona curzoniae) has adapted to the extreme environments of the highest altitudes of this region and exhibits tolerance to cold and hypoxia, in contrast to closely related species that inhabit the peripheral alpine bush or forests. To explore the potential genetic mechanisms underlying the adaptation of O. curzoniae to a high-altitude environment, we sequenced the heart tissue transcriptomes of adult plateau pikas (comparing specimens from sites at two different altitudes) and Gansu pikas (O. cansus). Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed genes (DEGs) and their primary functions. Key genes and pathways related to high-altitude adaptation were identified. In addition to the biological processes of signal transduction, energy metabolism and material transport, the identified plateau pika genes were mainly enriched in biological pathways such as the negative regulation of smooth muscle cell proliferation, the apoptosis signalling pathway, the cellular response to DNA damage stimulus, and ossification involved in bone maturation and heart development. Our results showed that the plateau pika has adapted to the extreme environments of the QHTP via protection against cardiomyopathy, tissue structure alterations and improvements in the blood circulation system and energy metabolism. These adaptations shed light on how pikas thrive on the roof of the world.