One-carbon metabolism (OCM) is a biological process that facilitates the transfer of one-carbon units crucial for several physiological functions including the synthesis of neurotransmitters. The normal regulation of the OCM pathway is maintained by the synergy between genes and the environment (nutrients). Disruptions in this pathway due to gene mutation or environmental alteration can adversely affect the mental health of an individual. Mostly, the genetic research on depression related to the OCM pathway is limited only to a few genes like MTHFR, MTR, and COMT. However, other important genes involved in this metabolic pathway, for example, DHFR, FOLH1, TCN2, TS, MTRR, and CBS, may also play a significant role in influencing depression pathology. This chapter summarizes the current knowledge on the relationship between key candidate genes of the OCM pathway and depression. Subsequently, it explores the plausible mechanism underlying their association and highlights the genetic variation and susceptibility to depression across diverse populations.