Several marine dinoflagellates produce unique secondary metabolites with intriguing biological activities, eliciting anticancer, antiepileptic, anti-inflammatory, or anti-microbial responses in various cell types. Among these known compounds are phycotoxins, such as the linear and cyclic polyethers considered as potential therapeutants due to their complex alternative mode of action as ion-channel effectors or enzyme inhibitors capable of modifying diverse intracellular signaling pathways. Yessotoxin (YTX) and analogs are polyketide-derived polycyclic toxins produced by certain species of marine dinoflagellates, Protoceratium reticulatum, Lingulodinium polyedra, and Gonyaulax spinifera, and are structurally related to ciguatoxins and brevetoxins with potent ion-channel activity. The over-expression or aberrant function of ion channels is considered a channelopathy, and critical pathologies in different intracellular signaling pathways that involve receptors such as voltage-gated ion-channels, particularly voltage-gated sodium channels (Na_V), are exhibited in response to exposure to such toxins. In the search for innovative therapeutants, this study aimed to evaluate the affinity of YTX for the Na_V1.5 channel, using in silico modelling tools. This approach allowed for identification of these interactions and determination of the respective free-binding energies. Our results showed significant interactions and low binding free energies (ΔG), between -6.79 and -10.32 Kcal mol^-1 for YTX in the Na_V1.5 protein model. Certain amino acid residues in Domains I and II were reached, indicating that this toxin is a potential Na_V 1.5 modulator. This study constitutes the first approach to in silico exploration of polyketide-derived dinoflagellate toxins in pursuit of evaluating their therapeutic potential.