Berries of Northern European bogs and forests (Vaccinium spp.) contain significant quantities of various phenolic compounds. Most of these compounds are recovered when berry juice is produced. However, a considerable part of polyphenols remains in berry press residues and are discarded as food industry waste. The aim of the study was to compare the methods of extraction of polyphenols from press residues of American cranberry and optimize the extraction conditions. The impact of main extraction parameters (e.g., extraction time, solid/solvent ratio, solvent type) on the yield of extracted polyphenols was examined. Ultrasound-assisted extraction showed the highest potential from all studied methods, given its fast, convenient use and low cost it was possible to recover up to 5 g of polyphenolics from 100g of berry press residues (bilberry). Response Surface Methodology (RSM) was used to identify the optimal solvent composition for extraction, which was found to be 70% ethanol in combination with 1% formic acid. Antimicrobial activity of extracts was evaluated by the Agar Diffusion Method, which showed a potential use of extracts to inhibit growth of human pathogens in concentrations <0.0125 mg/L. Proliferation of human dermal fibroblasts was inhibited, and cell cytometry showed high antiradical activity in vitro, which was 2 times higher than that of Vitamin-C. The purified polyphenol extracts contained up to 15 different anthocyanins and 150 other polyphenols (identified by Orbitrap-MS) of which 37 were quantified and used for chemotaxonomic analysis. Taken together, these results put the waste product- berry press residues- as a valuable source of compounds that can be used to develop new nutraceuticals and functional foods with various health benefits.