Neuroinflammation, characterized by production of proinflammatory cytokines and other toxic / protective molecules followed by the activation of glial cells and the infiltration of immune cells, is involved in the pathomechanism of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Elevated level of transforming growth factor-β1 (TGF-β1), an anti-inflammatory cytokine, has been observed in the peripheral blood and the cerebrospinal fluid of ALS patients. However, the exact role of TGF-β1 in ALS has not been elucidated. We show that TGF-β1 level is elevated in activated astrocytes of the lumbar spinal cord of of mutant superoxide dismutase 1 (SOD1^G93A) mice and that astrocyte-specific overproduction of TGF-β1 in SOD1^G93A mice accelerates later disease progression in a non-cell autonomous manner with deactivated microglia, and fewer infiltrated T cells, leading to reduced IGF-I and CD11c expressions of microglia. On the other hand, we also show that astrocyte-specific downregulation of mutant SOD1 in SOD1^G37R mice slows later disease progression with lower levels of TGF-β1. Moreover, endogenous TGF-β1 levels in SOD1^G93A mice negatively correlate with survival time. These findings indicate that astrocyte-derived TGF-β1 is a determinant of the disease progression of ALS mice by regulating the neuroprotective inflammatory response by microglia and T cells. Furthermore, targeting TGF-β1 in the cell-type specific manner can be a viable therapeutic candidate in ALS.