A new heterogeneous acid catalyst based on a natural resource, Tunisian clay (Clay-H0.5), has been prepared and characterized by FT-IR, FE-SEM, and powder X-ray diffraction (XRD), as well as chemical composition, cation exchange capacity, specific surface area, and pore volume. Acid treatment for 0.5 h enlarged the surface area from 78.24 to 186.10 m(2)/g and pore volume (PV) from 0.186 to 0.281 cm(3)/g. The catalytic activity of this material was investigated in ketalization reaction under mild solvent-free conditions. This achieved up to 92% isolated yield for only 10 wt.% of the catalyst. This environmentally friendly method has advantages such as simple work-up procedure, avoidance of organic solvents, and good performance in ketalization reactions. Importantly, the Clay-H0.5 catalyst showed good recyclability where insignificant activity loss was exhibited even after six runs. Synthesized cyclic ketals were tested for their possible antileishmanial and antibacterial activities as well as antifungal activity. Biological screening showed that compound 11 had important antileishmanial activity against both L. major and L. infantum, while compound 14 also had significant antibacterial activity against four gram-positive and two gram-negative bacteria, and antifungal activity against Candida albicans, with minimal inhibitory concentration values ranging from 15.62 mu g/mL to 125 mu g/mL.