Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that impacts neurons in the brain and spinal cord. Although a substantial number of studies have been conducted, much remains to be learned about the cellular mechanisms underlying ALS. In this study, we employed an engineered ascorbate peroxidase (APEX)-based proximity biotinylation, together with affinity pull-down of the ensuing biotinylated peptides, to investigate the proximity proteomes of human SOD1 and its two ALS-linked mutants, G85R and G93A. We were able to identify 25 common proteins with preferential enrichment in the proximity proteomes of SOD1G85R and SOD1G93A over wild-type SOD1. Our co-immunoprecipitation and Western blot analyses showed stronger binding of the two SOD1 mutants toward one of these proteins, SRSF2, than the wild-type counterpart. We also observed aberrant RNA splicing of three neurodegeneration-associated and SRSF2-regulated genes, including EIF4A2, SETX, and MELK, in cells with ectopic expression of the two SOD1 mutants relative to cells expressing the wild-type protein. The differences in splicing elicited by the SOD1 variants were markedly attenuated upon knockdown of SRSF2. Collectively, we uncovered that ALS-liked SOD1G85R and SOD1G93A mutants interact more strongly with SRSF2, and the aberrant interactions perturbed mRNA splicing. Thus, our work offered novel mechanistic insights into the contribution of the ALS-linked SOD1 mutants to disease etiology.