The benzylation reaction of curcumin and tetrahydrocurcumin (THC) with benzyl bromide and potassium carbonate in acetone was investigated. It was found that curcumin undergoes O-alkylation first, followed by C-1 substitution. In contrast, THC undergoes these reactions in reverse order, which was further explained by DFT calculations showing a clear energetic preference (19.5 Kcal/mol) for the C-1 versus the O-alkylation reaction of THC. In addition, the antioxidant activities on lipid peroxidation and cytotoxic activities of both benzylated derivatives were studied, showing that the C-dibenzylated curcuminoid (C-DiBn, 2b), exerts a superior activity than both tribenzylated (TriBn, 2c) and tetrabenzylated (TetraBn, 2d) curcuminoid derivatives in both essays. A DFT theoretical study to explain the experimental results and the preferences for the nucleophilic attack between the phenolic oxygen or C-1 anions was conducted. Furthermore, docking calculations on a DNA fragment shed light on the potential factors affecting the biological activity of these benzylated curcuminoids.