Lou Gehrig's disease or amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the progressive and selective death of motor neurons in the cerebral cortex, brainstem and spinal cord, resulting in extensive paralysis and death of the patient within 3–5 years after onset. Adult mesenchymal stem cells (MSCs) exhibit neuroprotective properties when introduced into the degenerating central nervous system through different putative mechanisms including secretion of growth factors and transdifferentiation. Herein, we injected MSCs into the cerebrospinal fluid of symptomatic hSOD1^G93A rats, a transgenic animal model of familial ALS, expressing a mutated form of the human superoxide dismutase. MSCs were found to infiltrate the nervous parenchyma and migrate substantially into the ventral grey matter where motor neurons degenerate. Even though overall astrogliosis was not modified, MSCs differentiated massively into astrocytes at the site of degeneration. The intrathecal delivery of MSCs and the subsequent generation of healthy astrocytes at symptomatic stage decreased motor neuron loss in the lumbar spinal cord, preserving motor functions and extending the survival of hSOD1^G93A rats. This neuroprotection was correlated with decreased inflammation, as evidenced by a lower proliferation of microglial cells and a reduction of COX-2 and NOX-2 expression. Together, these data highlight the protective capacity of adult MSC-derived astrocytes when grafted into the central nervous system and illustrate an attractive strategy to target excessive inflammation in ALS.