Systemic lupus erythematosus (SLE) is an autoimmune disease associated with the production of double-stranded DNA (dsDNA) antibodies and other antibodies, that predominantly affects women, with a wide range of lesions. Although neuropsychiatric lupus erythematosus (NPSLE), characterized by neuropsychiatric symptoms related to cerebrovascular diseases or depression, ranks high in severity, and no specific treatments have yet been defined. 2-carba cyclic phosphatidic acid (2ccPA) is a derivative of cyclic phosphatidic acid isolated from a true slime mold Physarum polycephalum in 1992. Treatment with 2ccPA reportedly suppresses neuroinflammation and promotes tissue repair in mouse models of multiple sclerosis and traumatic brain injury. We performed behavioral tests in MRL/lpr mice as a model of NPSLE. The mice showed increased depression-like behaviors and decreased emotional responses to a new environment compared to the control mice. Treatment with 2ccPA significantly suppressed the behavioral abnormalities in MRL/lpr mice. In the prefrontal cortex and hippocampus, MRL/lpr mice showed a significantly elevated expression of CD68, a M1 phenotypic marker of microglia, which was significantly suppressed by 2ccPA treatment. In contrast, the expression of Arginase-1, a M2 phenotypic marker of microglia, was significantly increased by 2ccPA treatment. MRL/lpr mice showed higher plasma levels of anti-dsDNA antibody, which is mainly involved in the pathogenesis of SLE, compared to control mice. Treatment with 2ccPA decreased these levels in the MRL/lpr mice. These results suggest that 2ccPA treatment promotes phenotypic switch of M1 microglia to M2 and suppresses behavioral abnormalities in MRL/lpr mice.