In this application note, we present the development of a MS-compatible UPLC method for the simultaneous determination of eight active pharmaceutical ingredients (APIs) found in common over-the-counter (OTC) cold and flu medication. These APIs include acetaminophen, dextromethorphan hydrobromide, phenylephrine hydrochloride, chlorpheniramine maleate, ibuprofen, pseudoephedrine hydrochloride, duaifenesin, and doxylamine succinate. A systematic protocol that includes scouting, screening, and optimization steps is employed to ensure faster and more effective development of robust and reproducible method. Results from each step are analyzed using custom calculations and custom reports of the Empower 3 Chromatographic Data Software. Both the UV and mass spectral data from the ACQUITY QDa Mass Detector is utilized for accurate identification and tracking all of the components during the development process. Finally, the developed method is used to analyze commercially available over-the-counter cold and flu medication.