Background: Polypharmacy is common in headache medicine. This project uses DrugBank and Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) to determine the likelihood of a theoretical and empirically reported interaction between a given number of headache abortive and preventive medications. Methods: All headache medications referenced in “The American Headache Society Position Statement on Integrating New Migraine Treatments into Clinical Practice” and Szperka’s “Migraine care in the era of COVID-19: clinical pearls and plea to insurers” were included. All possible combinations of up to three abortives and preventatives were screened for drug-drug interactions through searches in DrugBank and FAERS. If at least one drug-drug interaction was listed, then it was included in our analysis. The percentage of combinations containing an interaction was then compared across the two databases. Results: Of the 38 abortives and 23 preventives included, once more than 3 drugs are used in any combination, a drug-drug interaction was >99% likely, per DrugBank. However, per FAERS, the reported interaction was 39% to 60% likely once 3 or 4 drugs are used in any combination. In FAERS, the likelihood of interaction rised most dramatically once 3 or more drugs are used. Conclusions: Theoretical interactions, based on DrugBank, maybe overstated when compared to actual observed interactions in FAERS. Future direction is needed delving into the types of interactions recorded in each database.