BACKGROUND Pistachio shell is a lignocellulosic biomass with a high potential to be converted into chemicals, biopolymers, and biofuels. Alkaline pre‐treatment is an effective way to extract hemicellulose and increase the cellulose hydrolysis. However, there are some disadvantages to this process, such as a long processing time and the formation of high amounts of degradation products. Microwave irradiation can be used to enhance the effectiveness of alkaline treatment. In this study, microwave‐assisted alkali pre‐treatment (MAAP) was carried to fractionate pistachio shell into its valuable components (i.e., hemicellulose and cellulose), and the enzymatic hydrolysis of cellulose‐rich residues was performed to produce fermentable sugars. RESULTS The MAAP conditions (microwave power, NaOH concentration, and pre‐treatment time) were studied and optimized by Box–Behnken design to obtain the highest hemicellulose and cellulose yields. Optimal pre‐treatment conditions were microwave power of 224 W, NaOH concentration of 1.96 N, and pre‐treatment time of 2.63 min. Under these conditions, the recoveries were 58.35% and 92.46% for hemicellulose and cellulose, respectively. Additionally, compositional analysis carried out on the solid and liquid fractions obtained from the pre‐treatments indicated that the main components in the liquid phases were xylooligosaccharides (XOS) and the solid phases were enriched in cellulose. MAAP enhanced the enzymatic hydrolysis yield, and a maximum glucan to glucose conversion yield of 82.67 mol% was obtained for the solid pre‐treated under optimum conditions. CONCLUSION The studied MAAP process could be an effective and viable option to extract hemicellulose from pistachio shell and increase the enzymatic digestibility of cellulose‐rich solid residues. © 2020 Society of Chemical Industry (SCI)