Herein, ZSM-5 zeolites of several Si/Al mole ratios, and varying hydrophobicity were used as catalysts in the ketalization of glycerol. The water formed in the reaction adsorbs on acidic sites, hampering the catalytic conversion of glycerol. The conversion drops even more by adding water in the reaction mixture, intensifying the adsorption in hydrophilic zeolites. However, the samples with the higher Si/Al ratio and abundant hydrophobic Si-O-Si linkages had the uppermost turnover frequency. The reaction proceeds at the interface of the glycerol and acetone phases. Since the catalyst preferentially stays in the glycerol phase due to gravity action, the full catalytic action of the catalyst is hindered. Contact angle measurements with the glycerol/zeolite systems confirmed that the hydrophobic zeolite had the lowest affinity with glycerol, thus improving the interfacial solubilization of glycerol/acetone in the vicinity of active sites turning it much more efficient. The catalytic action was further enhanced by partially ion-exchanging external acid sites with minor quantities of bulky n-hexylammonium cations, turning the zeolite more hydrophobic and a strong candidate for other acid-catalyzed interfacial liquid-phase reactions.