In this study, the catalytic activity of calcined M3Al (M: Sr, Cd, Ni, Co, and Ca) and the efect of replacing divalent cations with Ca2+ in calcined MxCa3−xAl hydrotalcite on the catalytic conversion of benzaldehyde and acetophenone to chalcone via Claisen–Schmidt condensation has been investigated. A series of M3Al and MxCa3−xAl were synthesized by the coprecipitation method and characterized by SEM, BET, FT-IR, EDS, XRD, CO2-TPD techniques, and the Hammett indicator method. The results showed that the synthesized samples have normal surface area, high crystallinity, and three types of moderate, strong, and stronger basic sites. The catalytic activity is efectively dependent on the number of stronger alkaline sites. The efects of diferent parameters such as calcination temperature, solvents, catalyst amount, catalyst reusability, and the efects of electron-donating and electron-withdrawing groups were investigated. In optimum conditions over 0.04 wt% Sr0.5Ca2.5Al catalyst, at atmospheric pressure, 60 °C, in ethanol, yield (%) of chalcone was achieved at 87%.