New 5‐cyano‐6‐oxo‐pyridine‐based sulfonamides (6a–m and 8a–d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5‐cyanopyridine derivatives 6e and 6l on cell‐cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.