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Dendritic spines are essential for synaptic transmission, neural circuit organization, and cognitive function. Their morphology and density influence synaptic plasticity, learning, and memory. Many proteins in dendritic spines are modified with O-GlcNAc, a monosaccharide that can be attached and removed from serines and threonines. O-GlcNAc has been implicated in multiple brain disorders, yet the role of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc modification from proteins, in dendritic spine regulation remains unclear. This study examines the role of OGA in spine and synapse morphogenesis. Immunohistochemical and biochemical analyses reveal that OGA is present in dendritic spines. Functional assays show that OGA promotes spine maturation, increases spine density, and alters synapse size. Additionally, OGA modulates the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), down-regulating GluA2-containing receptors in developing and mature neurons. These findings highlight OGA as a key regulator of excitatory synaptic remodeling and a therapeutic target for synapse-related pathologies such as Alzheimer's disease and autism.