Mammalian / mechanistic target of rapamycin (mTOR) is a critical sensor of environmental cues that regulates cellular macromolecule synthesis and metabolism in eukaryotes. DNA methylation is the most well-studied epigenetic modification that is capable of regulating gene transcription and affecting genome stability. Both dysregulation of mTOR signaling and DNA methylation patterns have been shown to be closely linked to tumor progression and serve as promising targets for cancer therapy. Although their respective roles in tumorigenesis have been extensively studied, whether molecular interplay exists between them is still largely unknown. In this review, we provide a brief overview of mTOR signaling, DNA methylation as well as related serine and one-carbon metabolism, one of the most critical aspects of metabolic reprogramming in cancer. Based on the latest understanding regarding the regulation of metabolic processes by mTOR signaling as well as interaction between metabolism and epigenetics, we further discuss how serine and one-carbon metabolism may serve as a bridge that links mTOR signaling and DNA methylation to promote tumor growth. Elucidating their relationship may provide novel insight for cancer therapy in the future.