The benefits of mindfulness on human health are well-documented, but the mechanisms underlying these effects are not well-understood. Our aim was to identify molecular alterations related to mindfulness by profiling the epigenetic response in long-term meditators. We performed a genome-wide screen of DNA methylation by using the Illumina HumanMethylation450 platform in peripheral blood leukocytes from 17 long-term meditators and 17 matched controls. Top-ranked genes were validated by bisulfite cloning sequencing. Database for Annotation, Visualization, and Integrated Discovery and Ingenuity Pathways Analysis bioinformatic tools were used to characterize key processes underling the methylation changes. We found 64 differentially methylated regions (DMRs) in meditators compared to controls, corresponding to 43 genes. Most of the mindfulness-related DMRs (70.3%) were hypomethylated in meditators, and 23.4% of mindfulness-related DMRs clustered in telomeric chromosomal regions. Notably, almost half of the mindfulness-related DMRs (48.4%) involved genes linked to common human diseases, such as neurological and psychiatric disorders, cardiovascular diseases, and cancer. Lipid metabolism and atherosclerosis signaling pathway were significantly enriched in our set of DMRs. Functional in silico analysis also revealed tumor necrosis factor (TNF) and NF-κB signaling as crucial regulators of the mindfulness-related genes. Our study suggests that there is a consistent epigenetic response to long-term meditation practice in blood leukocytes with predominant loss of cytosine-phosphate-guanine methylation in distinct genomic regions, such as telomeres. Further research is warranted to confirm that the molecular response to mindfulness practice involves crucial transcriptional regulators related to a wide range of human common diseases, such as TNF and NF-κB.