Amyotrophic lateral sclerosis (ALS) is a calamitous neurodegenerative disorder characterized by denervation of upper and lower motor neurons. Numerous hypotheses suggest that toxic protein misfolding and aggregation cause ALS, similar to that of other neurodegenerative diseases, such as Alzheimers and Parkinsons. Protruding causes of familial ALS are mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1), which decrease protein stability and endorse protein aggregation. Thus, the interference concerning aggregate formation and destabilization in SOD1 is considered to be an impending therapeutic strategy. In this work, we utilized computational chemistry methods to initially study the effect of substitution mutation, His46Arg on SOD1 protein. Further, we described the interaction of two naturally occurring polyphenol compounds, naringin and naringenin with mutant SOD1 that is regarded to hinder the protein aggregation. Subsequently, the use of quantum chemical and molecular mechanics calculations speculated that naringin had a strong binding affinity with mutant SOD1 and impeded the formation of toxic aggregates than that of naringenin. Ultimately, we could conjecture that ingesting of polyphenol-rich foods in ALS patients may be regarded to improvise their living. Moreover, the findings from our study could pave a way in the field of structure-based drug design in developing potential anti-aggregation inhibitors against incurable ALS, affecting the human population.