The human voltage-gated sodium (Nav) channel, hNav1. 5, is predominantly expressed in cardiac myocytes and is responsible for the rapid upstroke of the cardiac action potential. hNav1. 5 channel plays a central role in congenital and acquired cardiac arrhythmias and has been a key target for drug development. Mutagenesis studies have previously identified key residues in Nav channels S6 segments from central pore that form a receptor site for binding of local anesthetic and antiarrhythmic drugs. However, the structural details of how these drugs affect Nav channel function are not well understood. In this study, we used Rosetta computational modeling software to build a homology model of human Nav1. 5 in open-inactivated and closed states based on the cryo-EM structures of electric eel Nav1. 4 (PDB ID: 5XSY) and American cockroach NavPaS (PDB ID: 5X0M), respectively. We applied the RosettaLigand molecular docking program to study hNav1. 5 channel interactions with local anesthetic and antiarrhythmic drugs, including lidocaine, etidocaine, QX-314, ranolazine, flecainide, and GS967. Our lowest energy models have shown that both local anesthetic and antiarrhythmic drugs bind to hNav1. 5 via a common receptor site formed by S6 segments from domains III and IV in the central pore. Our results may further advance structural understanding for molecular mechanisms of local anesthetic and antiarrhythmic drug interaction with hNav1. 5 and provide useful insights towards the rational design of novel modulators of ion channel activity for the treatment of cardiac arrhythmias.