Aberrant aggregation in proteins leads to increased propensity of β-sheets, thereby increasing the toxicity level. Numerous neurological disorders are triggered due to aggregation in protein. Superoxide dismutase 1 (SOD1) is one such protein that leads to familial amyotrophic lateral sclerosis, a devastating neurodegenerative disorder. In our study, the aggregation effect in native and the fatal mutant (Ala4Val) SOD1 was examined, using tCONCOORD. Experimental studies reported that the naturally obtained polyphenol has an inhibitory effect on the aggregated protein. Consequently, we predominantly focused on curcumin, a natural occurring polyphenol, to inhibit the aggregation in SOD1. In view of that, curcumin was computationally docked with both the native and mutant SOD1, using Autodock. Thus, our analysis suggested that curcumin showed an enhanced binding affinity in the mutant SOD1 with increased hydrophobic interactions as compared to native SOD1. Further investigations were accomplished, using steered molecular dynamics and conformational sampling on both the bound complexes of native and mutant SOD1 with curcumin to unravel the effect of disaggregation. In addition, we also elucidated the variations in the free energy landscape of native and mutant SOD1 in their unbound and bound states to differentiate the aggregation. Hence, the study postulated a classical treatment against mutant SOD1, using the naturally occurring polyphenol (curcumin) via the computational framework for designing therapeutics against ALS.