The aim of this study was to determine the composition and content of phenolic compounds in ethanol extracts of eight different cultivars of American cranberry (Vaccinium macrocarpon Aiton) fruit using spectrophotometric and UPLC-ESI-MS/MS analysis and to evaluate the antioxidant activity in vitro of these extracts. The highest total amount of phenolic compounds evaluated via Folin–Ciocalteu spectrophotometry was detected in American cranberry fruit samples of the ‘Bain’ clone, and the highest total amount of flavonoids was found in samples of the ‘Drever’ and ‘Baiwfay’ cultivars. The highest total amount of the individual phenolic compounds (519.53 ± 25.12 mg/g DW) identified and quantitatively evaluated via chromatography was detected in samples of the ‘Searles’ cranberry cultivar. In the studied cranberry samples, the predominant phenolic compounds were hyperoside, quercetin, and procyanidin A2, while the amounts of other compounds were significantly lower. HCA and PCA revealed that ‘Woolman’, ‘Holliston’, ‘Pilgrim, and ‘Searles’ fruit samples had different quantitative content of phenolic compounds from other cranberry cultivars. Meanwhile, fruit of ‘Baiwfay’, ‘Drever’, ‘Bain’, and ‘Bergman’ were similar in their phytochemical profile.