A series of novel hybrid 8-hydroxyquinoline-indole derivatives (7a–7e, 12a–12b and 18a–18h) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ_1–42 aggregation as potential treatments for Alzheimer’s disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ_1–42 aggregation as 18c, 18d and 18f (EC₅₀ = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (1, EC₅₀ = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ_1–42 aggregation in the presence of Cu²⁺ or Zn²⁺ ions was also dramatically decreased by treatment with 18c, 18d and 18f. The most potent hybrid compound 18f afforded 82.3% and 88.3% inhibition, respectively, against Cu²⁺- induced and Zn²⁺- induced Aβ_1–42 aggregation. Compounds 18c, 18d and 18f were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP_Sw cells. Molecular docking studies with the most active compounds performed against Aβ_1–42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, π–π stacking interactions and π–cation interactions with Aβ_1–42, which may inhibit both self-aggregation as well as metal ion binding to Aβ_1–42 to favor the inhibition of Aβ_1–42 aggregation.