In view of the limited information available in the literature concerning leaves as by-products of Prunus armeniaca cultivation, the aim of this work was to identify and characterize their principal polyphenolic constituents by LC-ESI-QTOF-MS/MS and screening in vitro biological potency as antioxidant capacity (ABTS, online ABTS, FRAP, ORAC), antidiabetic (α-amylase, α-glucosidase), anti-obesity (pancreatic lipase), anti-cholinesterase (AChE and BChE), and anti-inflammatory (COX-1 and COX-2) inhibitory activity. Comparison of different polyphenolic extracts of P. armeniaca cultivar leaves according to their quantitative composition revealed them to be exceptional sources of hydroxycinnamic acids, and to a lesser extent as sources of flavonols. Polyphenol-rich apricot leaf extract (PrALe) showed the most effective anti-obesity action through inhibition of pancreatic lipase, COX-1 and antioxidant capacity, especially the oxygen radical absorbance capacity, which was particularly correlated with polyphenolic compounds. Online ABTS radical UPLC-PDA-PDA analysis clearly demonstrated that the three predominant compounds of PrALe are quercetin-3-O-rutinoside > 5-O- and 3-O-caffeoylquinic acid, which basically contribute to antioxidant potential. These results assist in the evaluation of plant sources of potential new raw materials for application in different commercial sectors, especially for food, cosmetics and pharmaceuticals production.