The methylation of DNA, RNA, and histone is a fundamental mechanism of epigenetic regulation, involving the addition of a methyl (CH3) group to these biomolecules through the formaldehyde cycle. This process frequently alters gene function via chromatin remodeling. Methylation of DNA, RNA, and/or histone is regarded as a critical step in memory formation. As a methyl donor for the methylation of DNA, RNA, and histone, formaldehyde acts as an epigenetic factor participating in this reversible and dynamic methylation process. During DNA demethylation, formaldehyde is produced in both dividing cells and post-mitotic neurons. Notably, endogenous formaldehyde levels increase in aging populations, whereas DNA methylation may decrease. This correlation suggests a close link between learning-responsive DNA methylation and memory formation. Moreover, abnormal metabolism of endogenous formaldehyde, impacting DNA, RNA, and histone methylation, is implicated in age-related cognitive decline. The concentration of formaldehyde positively correlates with cognitive impairments, such as Alzheimer’s disease (AD) and post-stroke dementia (PSD). Dysregulation of DNA, RNA, and/or histone methylation disrupts adult hippocampal neurogenesis (AHN) and contributes to memory deficits in AD patients and mouse models. Circadian disruptions are common in AD patients, and the methylation of clock genes, such as PER1 and CRY1, is closely associated with memory loss. Hypermethylation of these clock gene promoters may contribute to cognitive dysfunction. In rats, enhancing DNA demethylation or inhibiting DNA re-methylation results in spatial memory deficits during memory formation. However, scavenging elevated formaldehyde levels effectively alleviates memory loss in rats. In this chapter, we delve into the role of endogenous formaldehyde in the methylation and demethylation of DNA, RNA, and histone, as well as its impact on memory formation and loss.