Type 2 spastic paraplegia (SPG2) is a rare genetic disorder caused by null mutations in the gene encoding for the proteolipid protein 1, essential for myelin sheath formation around nerve fibers in the central nervous system (CNS). SPG2 manifests as progressive stiffness and weakness in the legs, accompanied by white matter abnormalities and axonal degeneration in the CNS. These myelin abnormalities impair neural communication, impacting motor function, cognition and may contribute to neuropsychological conditions like anxiety. Leriglitazone, a brain-penetrant PPARγ full agonist, has shown beneficial effects promoting myelination in preclinical models of rare neurodegenerative diseases like Adrenoleukodystrophy and other neurodegenerative and neuroinflammatory diseases with demyelination and associated loss of cognitive function. This study aimed to assess leriglitazone’s effects in Plp KO mice, a model for SPG2, focusing firstly on behavioral changes, gliosis reduction, and secondly, in vitro, on neuroplasticity enhancement. Leriglitazone treatment reduced anxiety in vivo as measured by behavioral tests, improved muscular strength and locomotion, and tended to decrease microgliosis and astrogliosis. Additionally, leriglitazone treatment increased the number of neurons and neurite network, as well as the number of synapses in mature neurons. These findings suggest leriglitazone’s broader impact beyond motor function improvement and highlight its potential in alleviating cognitive deficits and anxiety associated with SPG2. Further investigations into the molecular mechanisms underlying leriglitazone’s effects on neuroplasticity and its relationship with cognition and anxiety, are warranted. Understanding these mechanisms could enhance the therapeutic strategy involving leriglitazone for targeting SPG2 and related demyelinating disorders with neuropsychiatric deterioration.