Liquid chromatography coupled to low-resolution mass spectrometry (LRMS) has historically been a popular approach for compound quantitation. Recently, high-resolution mass spectrometry (HRMS) technical developments led to the introduction of new approaches for quantitative analysis. Whereas the performances of HRMS have been largely assessed for qualitative purposes, there are still questions about its suitability for quantitative analysis. Several papers on LRMS and HRMS comparison have been published; however, none of them was applied to polyphenol quantitation. In this work, a comparison between HRMS, operated in data-dependent acquisition mode, and LRMS, operated in selected-reaction-monitoring mode, was performed for polyphenol quantitation in wine. The two techniques were evaluated in terms of sensitivity, linearity range, matrix effect, and precision, showing the better performances of HRMS. The suitability of HRMS for quantitation purposes as well as qualitative screening makes HRMS the new technique of choice for both targeted and untargeted analysis.