Neurodegenerative disorders largely affect individuals at an advanced age; however, early-onset neurodegenerative diseases have also been reported. Alzheimer’s disease (AD) is the most common neurodegenerative disorder that affects millions of people worldwide, along with Huntington’s disease, Parkinson’s disease (PD), multiple system atrophy, and progressive supranuclear palsy. The etiology and pathological mechanisms of neurodegenerative disorders are diverse; however, dysregulated epigenetic modifications have frequently been observed in these disorders. In AD, DNA methylation is extensively suppressed in the neuronal cells of the affected regions. Similarly, abnormal DNA methylation pattern has been associated with dopaminergic neuron degeneration in PD. Besides, alterations in histone modification patterns have also been reported in the brains of animal models as well individuals with neurodegenerative disorders. Thus, targeting the epigenetic regulators is one of the strategies for managing and treating neurodegenerative diseases. Plant-derived natural compounds hold an immense potential in the field of drug discovery, as these compounds are abundantly available and exhibit minimal to no side effects. The anticancer, anti-diabetic, anti-inflammatory, cardio-protective, hepato-protective, and anti-obesity qualities of these substances have all been thoroughly investigated. Mechanistically, these natural compounds can modulate diverse cellular processes, including transcription, oxidative stress, translation, cellular trafficking, and post-translational modification. A large group of herbal natural compounds are shown to regulate the activity of several epigenetic regulators. By modulating the activity of specific epigenetic regulators, these natural compounds can revert the epigenetic signatures, thereby preventing neurodegenerative disease progression. This chapter discusses the possible role of natural compounds as epigenetic modulators in neurodegenerative conditions.