Alkaline pretreatments are considered highly effective for the separation of the different components of lignocellulosic biomass. However, cold alkaline extraction (CAE) exhibits minimal modification/degradation of hemicellulosic fraction and successfully accomplishes efficient delignification. In this research, the fast-growing clone AF2 of Populus x euramericana wood was utilized as the raw material and subjected to ultrasound-assisted CAE. The objective of incorporating ultrasound into cold alkaline extraction is to increase the yield of a hemicellulosic-rich liquid phase that can be used to produce high-value products such as furfural or xylitol. Simultaneously, it aims to obtain a solid phase with a higher calorific value compared to the raw material. The results, obtained from a central composite factorial design, demonstrated that the CAE process for 90 min at a sodium hydroxide concentration of 100 g L−1, a temperature of 30 °C, and with ultrasound assistance maximized hemicellulose extraction in the liquid phase (60.8% was extracted) and improved the heating value of solid phase.