Almond skin is an important by-product in the almond processing industry, rich in potentially health-promoting phenolic compounds. The objective of this present study is to separate the skin from the almond and extract its polyphenol contents using Ultrasound-Assisted Extraction (UAE) at room temperature. Optimization was performed according to a two-variable central composite design (CCD), and the optimum combination of ultrasonic intensity and extraction temperature was obtained through multi-response optimization: ultrasonic intensity (UI), 9.47W.cm2; and temperature, 20°C for an extraction time of 20 min. Under the above-mentioned conditions, total phenolic content was 258% higher with UAE than silent experiment. Mathematic modelling and microscopic investigations were achieved to enable understanding physical and structural effects of ultrasound on almond skins and comprehension of the mechanism behind the enhancement of mass transfer phenomena. Scanning Electron Microscopy (SEM) showed different acoustic cavitation impacts including fragmentation, sonoporation, and erosion. Extracts were analyzed by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), identifying a combination of flavanols, flavanones and non-flavonoids. UAE shows no negative effect on almond proteins and lipids when compared to natural almonds (NS).