Hibernation is a seasonal physiological state utilized by animals to conserve energy during winter. Hibernation is complex, involving large changes in metabolism and cellular function. During hibernation, many stress responses must be modulated to tolerate physiological challenges, such as malnutrition, oxidative stress, and hypoxia that would otherwise be lethal. To elucidate the changes in gene expression responsible for this remarkable phenotype in the central bearded dragon (Pogona vitticeps), total transcriptomic profiles were generated using RNA sequencing for brain, heart and skeletal muscle at three time points: 1) late hibernation, 2) two days post-arousal, and 3) two months post-arousal. Hibernation was associated with enrichment of stress response pathways, including cell cycle arrest mediated by p53, and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signalling. Epigenetic regulatory pathways, including chromatin modification and microRNA-mediated gene silencing were enriched during hibernation. Genes responsible for post-translational modification processes, such as ubiquitination, and sumoylation were also upregulated. Neuroprotective strategies were observed in the brain, including downregulation of a N-methyl-D-aspartate receptor, and increased expression of tau-protein kinase genes. In heart, genes involved in cardiac hypertrophy, including cardiac-specific transcription factors and actin cytoskeleton proteins, were upregulated during hibernation. In skeletal muscle, there was evidence for protection against muscle atrophy, increased antioxidant capacity, and enhanced mitochondrial metabolism. This study provides exciting insights into the molecular mechanisms that govern hibernation in the central bearded dragon, as well as adaptive responses of the brain, heart and skeletal muscle.