Layered double hydroxides (LDHs) act as catalysts in several reactions like in the cyanoethylation of alcohols with acrylonitrile to produce alkoxypropionitriles. Here we report an experimental and theoretical study in which it is shown that the experimental catalytic activity of LDHs in the cyanoethylation of 2-propanol and methanol correlates with the predicted strength of the basicity of the adsorbed surface species. First, it is shown that using activated LDHs containing Mg2+ and Al3+ (MgAl-LDH), Mg2+ and Ga3+ (MgGa-LDH), and Mg2+, Al3+ and Ga3+ (MgAlGa-LDH) great conversions to alkoxypropionitriles in high yields are obtained. Next, the basicity of these LDHs is estimated by means of the local softness, a local reactivity index calculated using density functional theory and appropriate surface models. For that, the adsorption of hydroxide and methoxide anions at the (001) surface of MgAl and MgGa-LDHs is investigated. We include LDHs containing Zn2+ and Al3+ (ZnAl-LDH) and Zn2+ and Ga3+ (ZnGa-LDH) in this part of the study to account for the effect of changing the divalent and trivalent metal composition on the basicity. It is found that hydroxide anions adsorbed on the MgGa-LDH surface and methoxide anions adsorbed on the MgAl-LDH surface are the most basic ones. This basicity trend correlates with our experimental findings about the catalytic activity of the activated LDHs. Further analyzing the connection between the LDH composition and the anion basicity, it is argued that the key steps dictating the LDH catalytic activity are the alcohol deprotonation in the cyanoethylation of 2-propanol, as it has been previously suggested, and the methoxide anion attack to the acrylonitrile double bond in the methanol cyanoethylation reaction.