Axonal pathology represents an early pathogenic event affecting motor neurons in both familiar and sporadic forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The mechanism(s) by which axons degenerate in ALS are largely unknown. Numerous independent studies documented alterations in fast axonal transport (FAT), a major cellular process sustaining axonal health, in a wide variety of familial ALS (fALS) models, including transgenic mice expressing mutant forms of superoxide dismutase 1 (mSOD1). The potential disease relevance of these observations was highlighted by genetic evidence showing that mutations in motor proteins powering FAT suffice to cause axonopathy and degeneration of motor neurons, but a mechanistic basis linking mSOD1 to such deficits remained elusive. Filling this gap in our knowledge, our studies in isolated squid axons showed that the toxic effect of mSOD1 proteins on FAT involves abnormal activation of the protein kinase p38alpha (p38α) and aberrant phosphorylation of axonal proteins, including the motor protein kinesin-1 and neurofilaments. Although numerous reports spanning decades documented enhanced phosphorylation (and hence activation) of p38 kinases in ALS-affected tissues and mSOD1-based fALS mouse models, their potential contribution to axonal pathology elicited by mutant SOD1 in vivo remained unknown. We addressed this gap in our knowledge by examining specific contributions of p38α, the most abundant p38 isoform expressed in neurons. In this work, we used a genetic approach to promote ubiquitous attenuation of p38α signaling in transgenic SOD1G93A mice, an animal model where the axonal pathology phenotype of ALS is faithfully recapitulated. Remarkably, we found that genetically based attenuation of p38α signaling in SOD1G93A mice prevented degeneration of spinal cord axons and loss of spinal motor neurons at an age when motor deficits are already manifested in this model. Interestingly, this effect was not associated with changes in transgenic mSOD1 expression and glial activation. Collectively, our findings reveal a significant contribution of p38-alpha to mutant SOD1-induced axonal pathology and neuronal preservation, suggesting this kinase might represent a potential therapeutic target to treat ALS.