Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) severely impacts patients' quality of life and leads to a poor prognosis. The current therapeutic protocol, corticosteroid administration, can also induce neuropsychiatric disorders. FTY720 is an immunomodulator that selectively confines lymphocytes in lymph nodes and reduces autoreactive T cell recruitment to the central nervous system (CNS). This study aimed to identify a novel therapeutic strategy for NPSLE. B6.MRL-lpr mice were treated with oral administration of FTY720 (2 mg/kg) three times per week for 12 weeks, to evaluate its efficacy in a model of NPSLE. FTY720 significantly attenuated the impulsive and depression-like behavior of B6.MRL-lpr mice. Neuronal damage was reduced in the cortex, hippocampus, and amygdala of the FTY720-treated B6.MRL-lpr mice, as well as in TNF-α-treated HT22 cells. Additionally, FTY720 downregulated levels of inflammatory cytokines, and reduced the infiltration of T cells and neutrophils in the brain parenchyma. FTY720 also acted directly on cerebral endothelial cells and reduced the permeability of the blood-brain barrier (BBB) in B6.MRL-lpr mice, as evidenced by reduced central IgG and albumin levels. Finally, FTY720 significantly inhibited activation of PI3K/Akt/GSK3β/p65 signaling, which further reduced the expression levels of adhesion molecules in bEND.3 cells treated with B6.MRL-lpr mouse serum. Collectively, our data indicate that oral administration of FTY720 at an early stage has beneficial effects in NPSLE-model B6.MRL-lpr mice, suggesting that it may represent an effective new therapeutic strategy for NPSLE.