The current study provides a novel insight into the role of synergism of the changes in Mg²⁺/ Al³⁺ in the best catalytic activity of indol-3-yl derivatives. A series of Co-Mg-Al layered triple hydroxides (LTHs) catalysts were produced by altering the Al³⁺/Mg²⁺ ratio with respect to Co²⁺. The physicochemical properties of LTHs were well characterized by ICP-AES, XRD, FTIR, FE-SEM, BET, Zeta-sizer, and VSM. The results show that the sample CMA4 (Co²⁺:Mg²⁺:Al³⁺ 2:4:4) is an exception to the physicochemical characteristics of the produced Co-Mg-Al LTHs, which is due to the synergism between the changes in Mg²⁺ and Al³⁺. To the best of our knowledge, this is the first study to report the synthesis of indol-3-yl derivatives from indole-3-carbaldehyde using Co-Mg-Al LTHs as highly efficient heterogeneous catalysts, which is an extremely appealing path. The selectivity of the synthesis was studied by condensing various nucleophiles through the one-pot method that established superior reactivity under mild conditions. Notably, the results show that the Co-Mg-Al LTHs system exhibited an extraordinarily catalytic activity, with the highest yield (98%) being obtained under the following optimal conditions: the concentration of Co-Mg-Al LTHs = 5 mol%, 30 min., water/ethanol as solvent. Furthermore, the reusable studies exhibited that the catalysts were found to be stable and reusable for up to six cycles without substantial loss of catalytic activity. Finally, a plausible reaction mechanism of the Co-Mg-Al LTHs system for indol-3-yl derivatives was put forward according to our comprehensive analysis. Our work illuminates a cheap and flexible strategy for the synthesis of indol-3-yl derivatives using Co-Mg-Al LTHs.