In this work, an integrated approach for the identification of new antiviral agents from natural sources for the treatment of acute respiratory infections is presented. The approach comprises (i) the selection of starting material based on traditional knowledge, (ii) phenotypic screening of extracts for antiviral activity, and (iii) the implementation ofpredictions to identify antiviral compounds and derive the molecular mechanism underlying their biological activity. A variety of starting materials from plants and fungi was selected for the production of 162 extracts. These extracts were tested in cytopathic effect inhibition assays against influenza virus A/Hong Kong/68 (HK/68), rhinovirus A2 (RV-A2), and coxsackie virus B3 (CV-B3). All extracts were also evaluated regarding their cytotoxicity. At an ICthreshold of 50 µg/mL, 20, 11, and 14% of all tested extracts showed antiviral activity against HK/68, CV-B3, and RV-A2, respectively. Among all active extracts (n = 47), 68% showed antiviral activity against one of the investigated viruses, whereas 31% inhibited at least two viruses. Herein, we present a comprehensive dataset of probed extracts along with their antiviral activities and cytotoxicity. Application examples presented in this work illustrate the phytochemical workflow for the identification of antiviral natural compounds. We also discuss the challenges, pitfalls, and advantages of the integrated approach.