While the exact cause of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease is not completely understood, compelling evidence implicates the aggregation of specific proteins and peptides. Co-solvents can provide molecular insight into protein aggregation mechanisms and the chemical nature of potential aggregation inhibitors. Here, we study, through molecular simulations, the hydration and binding free energies of an amphiphilic peptide from the nonamyloid-β component (NAC), a key aggregation-prone domain of α-synuclein, in water and an 8 M aqueous urea solution. Isoleucine, glycine, and serine peptides of the same length are also studied to unravel the role of urea in the hydration and aggregation of hydrophobic and hydrophilic domains. A strong impact of urea in hindering the aggregation of the NAC subdomain is observed. A slightly weaker aggregation inhibition is observed for the Gly and Ser peptides, whereas a much lower aggregation inhibitory activity is found for the Ile peptide, seemingly contrasting with urea’s protein unfolding mechanism. This behavior is shown to derive from a lower profusion of urea next to the hydrophobic side chains and the backbone of the Ile’s peptide in the dimeric form. As a consequence, β-sheets, formed upon aggregation, remain nearly intact. Hydrophilic neighbor groups in the amphiphilic NAC subdomain, however, are shown to anchor enough urea to weaken hydrophobic interactions and disrupt β-sheet structures. Our results indicate that urea’s activity is potentiated in amphiphilic domains and that potential drugs could disrupt hydrophobic β-sheet-rich regions while not binding primarily to hydrophobic amino acids..