Angelman syndrome (AS) is a severe neurodevelopmental disorder with no effective therapies. Most of the behavioral deficits observed in AS patients arise from the absence of ubiquitin protein ligase E3A (UBE3A) in the brain during development, driven by the loss of maternally expressed UBE3A and silencing of the paternal copy of this gene through imprinting. Safe and effective therapies aiming at restoring the expression of the paternal UBE3A gene early in human life are currently lacking. In this study, we investigated whether octanoic acid (OA), a medium-chain fatty acid, could unsilence the paternal Ube3a allele in neurons and ameliorate the behavioral defects in a murine model of AS. To this end, Ube3a(m-/p+) and Ube3a(m+/pYFP) mice, as well as their wild-type littermates, were fed either a control or OA-supplemented diet from postnatal day 0 through adulthood, and the improvements in AS-related cellular and behavioral deficits were characterized. We demonstrate that dietary intake of OA activates the expression of the silenced, paternal Ube3a in neurons and improves select AS behavioral phenotypes in mice. We further show that downregulation of topoisomerase II beta and restoration of dendritic spine development may underlie the unsilencing of Ube3a and the behavioral improvements in OA-supplemented animals, respectively. Together, our findings suggest that dietary supplementation with OA could serve as an early, safe, and clinically feasible therapeutic strategy for reactivation of the paternal UBE3A allele in patients with AS.