Human (h) telomerase (TL; EC 2.7.7.49) plays a key role in sustaining cancer cells by means of elongating telomeric repeats at the 3' ends of chromosomes. Since TL-inhibitor (TI) stand-alone cancer therapy has been proven to be remarkably challenging, a polypharmacological approach represents a valid alternative. Here we consider a series of compounds able to inhibit both hTL and the tumor-associated carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII. Compounds <b>7</b> and <b>9</b> suppressed hTL activity in both cell lysates and human colon cancer cell lines, and prolonged incubation with either <b>7</b> or <b>9</b> resulted in telomere shortening, cell cycle arrest, replicative senescence, and apoptosis. Enzyme kinetics showed that <b>7</b> and <b>9</b> are mixed-type inhibitors of the binding of DNA primers and deoxynucleoside triphosphate (dNTP) to the TL catalytic subunit hTERT, which is in agreement with docking experiments. Compound <b>9</b> showed antitumor activity in Colo-205 mouse xenografts and suppressed telomerase activity by telomere reduction.