Background Domestic yaks play an indispensable role in sustaining the livelihood of Tibetans and other ethnic groups on the Qinghai-Tibetan Plateau (QTP), by providing milk and meat, and have evolved numerous physiological adaptabilities to high-altitude landscape, such as strong capacity of blood oxygen transportation and high metabolism. The role of DNA methylation and network of gene expression underlying milk production and adaptation to high altitudes of yak need further exploration. Results We performed genome-wide DNA methylome and transcriptome analyses of breast, lungs, and gluteal muscle from yaks of different ages. We identified differentially methylated regions (DMRs) across age groups within the each tissue, and breast tissue had considerably more differentially methylated regions than that from the three younger age groups. Hypomethylated genes with high expression level might regulate milk production by influencing protein processing in the endoplasmic reticulum. Weighted gene correlation network analysis revealed that the “hub” gene ZGPAT was highly expressed in post-mature breast tissue and that it potentially regulated the transcription of 280 genes, which play roles in regulating protein synthesis, processing, and secretion. Besides, Tissue network analysis indicates that high expression of HIF1A regulates energy metabolism in the lung. Conclusions The results of this comprehensive study provide a solid basis for understanding the epigenetic mechanisms underlying milk production in yaks, which could be helpful to breeding programs aimed at improving milk production.