Since the early days of migrainous research, serotonin receptors have been considered a major target of drugs, being among the most marketed one for its treatment. They are also involved in the mechanisms underlying many neurological dysfunctions. In this context, by taking advantage of their crystallographic structure co-crystallized with their agonist dihydroergotamine (DHE), one of the oldest and most widely used antimigraine drugs, a quantum chemistry study based on the electrostatically embedded molecular fractionation with conjugate caps scheme within the density functional theory formalism is performed to unveil this complex’s detailed binding energy. Furthermore, we predict the relevance of the DHE regions, as well as the influence of each protein segment to DHE–serotonin receptor binding. We believe that our work is a first step using in silico quantum design as a means to influence the discovery of new drugs to treat migraine and other diseases related to the serotonin agonist.