Emerging evidence suggests that histone modifications contribute to age-related cognitive decline. Our lab previously demonstrated that elevated H3K9me3 in aged mice leads to synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). Treatment with ETP69, a selective inhibitor of H3K9me3’s catalyzing enzyme (SUV39H1), was shown to restore synapses, BDNF and cognitive performance. However, the mechanism underlying H3K9me3 regulation is poorly understood. In this study, we investigated the role of age-associated stressors such as oxidative stress in H3K9me3 elevation. The oxidative stressor hydrogen peroxide elevated the SUV39H1 regulator SIRT1 but did not increase H3K9me3. The aged brain is also marked by reduced BDNF, and we found that inhibiting BDNF signaling by blocking the BDNF receptor TrkB elevates H3K9me3 in an age-dependent fashion. Antioxidant treatment prevented the H3K9me3 elevation by TrkB-Fc, suggesting that inhibiting BDNF signaling regulates H3K9me3 via an oxidative stress-based mechanism. We further investigated if exercise, which stimulates BDNF production, regulates repressive H3K9me3 at the promoters of neuronal plasticity genes. Exercise decreased H3K9me3 at BDNF promoter VI in aged mice and stimulated BDNF production. Similarly, SUV39H1 inhibition decreased H3K9me3 at BDNF promoter VI in aged mice and showed a corresponding increase in BDNF VI expression. Exercise and SUV39H1 inhibition differentially affected BDNF and GABRA2 expression in young and old mice. H3K9me3 promoter binding at all neuronal plasticity genes except for GABBR1 decreased as mice aged. Overall, our data suggests that H3K9me3 and BDNF are engaged in a negative feedback mechanism that is affected by physical activity, oxidative stress and age.