Monarda didyma L. (Lamiaceae) is a medicinal and aromatic herb native to eastern North America and now is also cultivated in Northern Italy, which shows terminal heads of bright scarlet-red flowers, subtended by a whorl of red-tinged leafy bracts. Starting from 2018, M. didyma flowering tops have been included in the Belfrit List of botanicals. However, to date studies on the crude extract of this plant are still lacking. The aim of the present study was to investigate the morphological and anatomical features of the flowering tops and the phytochemical profile of their ethanolic and hydroglyceric extracts (EE and HGE, respectively). HGE was the richest in total phenols (105.75 ± 5.91 vs. 64.22 ± 3.45 mg/100 mL) and especially in flavonoids (71.60 ± 5.09 vs. 47.70 ± 1.27 mg/100 mL), as confirmed also by LC-DAD-ESI-MS. Fifty-three polyphenols were identified and quantified. Even if they showed a common polyphenolic profile, EE and HGE showed quantitative differences. Flavan-3-ols and anthocyanins were the most expressed metabolites in HGE, whereas flavonols were the most expressed metabolites in EE. These features confer to HGE the highest antioxidant, anti-inflammatory, and anti-angiogenic properties, detected by several in vitro and in vivo assays, highlighting a promising use of this plant extract for skincare applications.