Among voltage-gated potassium channel (K) isoforms, K1.6 is one of the most widespread in the nervous system. However, there are little data concerning its physiological significance, in part due to the scarcity of specific ligands. The known high-affinity ligands of K1.6 lack selectivity, and conversely, its selective ligands show low affinity. Here, we present a designer peptide with both high affinity and selectivity to K1.6. Previously, we have demonstrated that K isoform-selective peptides can be constructed based on the simplistic α-hairpinin scaffold, and we obtained a number of artificial Tk-hefu peptides showing selective blockage of K1.3 in the submicromolar range. We have now proposed amino acid substitutions to enhance their activity. As a result, we have been able to produce Tk-hefu-11 that shows a half-maximal effective concentration (EC) of ≈70 nM against K1.3. Quite surprisingly, Tk-hefu-11 turns out to block K1.6 with even higher potency, presenting an EC of ≈10 nM. Furthermore, we have solved the peptide structure and used molecular dynamics to investigate the determinants of selective interactions between artificial α-hairpinins and K channels to explain the dramatic increase in K1.6 affinity. Since K1.3 is not highly expressed in the nervous system, we hope that Tk-hefu-11 will be useful in studies of K1.6 and its functions.