Pistachio trees show a clear response to low amounts of water supply. This experiment aims to follow the impact of partial root drying (PRD) on the phenolic compounds and fatty acids profile of the pistachio cultivars 'Mateur', 'Elguetar', 'Kerman' and 'Ohadi' grown in semi-arid conditions during the growing seasons of 2021 and 2022. The experiment orchard was located in the Regional Center of Agricultural Research of Sidi Bouzid (CRRA), Tunisia. Pistachio trees were subjected to three irrigation treatments from March to September, corresponding to T0: control irrigated at 100% crop evapotranspiration (ETc), T1: 75% ETc and T2: 50% ETc on a 15-day alternating cycle on one side of the root system. Results showed that reducing irrigation by 25% (75% ETc) compared to the control (100% ETc) increased water productivity mainly for the cv. 'Mateur' without significant reductions on yield, whereas the 50% ETc water regime clearly reduced the yield components. The two water regimes 75% ETc (T1) and 50% ETc (T2) enhanced the bioactive compounds content as compared to the control treatment (T0). Based on agronomic and nut quality parameters, it can be concluded that the PRD irrigation strategy is a very promising irrigation technique in pistachio trees to reduce water loss.