Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells' reactive phenotype.