In this study, two new Cu(II) complexes of p-tert-butylcalix[4]arene amide derivatives (8, 9) have been synthesised and investigated their DNA cleavage and antimicrobial activities. On the basis of spectral studies, a smaller distortion of square planar geometry has been proposed for both of the copper(II) complexes. The DNA cleavage studies show that the ligands are not efficacious, whereas the complexes have high activity. Futhermore, in order to determine the site of DNA cleavage, the DNA interactions of these compounds were investigated with some restriction enzymes. In addition, all synthesised compounds were screened for antimicrobial activities against some bacteria and for antifungal activities against yeast strains. The results showed that ethyl ester and furfuryl amide derivatives of the calixarenes are more efficient than other compounds against tested bacteria. However, complexes have not been effective. In case of DNA interaction studies, compounds were very effective against plasmid DNA.