Globe artichoke [Cynara cardunculus var. scolymus (L.) Fiori] is a proven source of nutraceutical compounds with high bioavailability. However, different pre- and post-harvest variables may affect plant secondary metabolism. In this view, the present study investigated the influence of irrigation frequency and drying temperature on the yield of dry leaf biomass and its pharmacological value in terms of polyphenol content. The field treatments included three irrigation frequencies (7, 14 and 21-day intervals) with a single dose of 10 mm water, and control (not irrigated). Artichoke biomass leaves were collected from 120-day plants and dehydrated using different air temperatures (30 °C, 40 °C, and 50 °C). The samples were analyzed for polyphenolic compounds by HPLC method. Antioxidant activity was also studied by ABTS, DPPH, and FRAP assays. Irrigation frequency significantly influenced the yield of dry leaf biomass with a greater increase in the case of irrigation frequency every 7 and 14 days than every 21 days. The content of caffeoylquinic acids (TCQA) was higher under soil water deficit conditions than in the raw material obtained from plants irrigated with different frequencies. The drought stress caused by the lack of additional irrigation increased the content of chlorogenic and ferulic acids in the biomass leaves. Higher drying temperatures (40 and 50 °C) increased the content of cynarine by 100% and 132% and ferulic acid by 100% and 172%, respectively, compared to biomass leaves dried at 30 °C. Irrigation frequency influenced the content of flavonoids, and frequency every 7 and 14 days than 21 days reduced apigenin and increased luteolin content. A high correlation between the content of TCQA and the frequency of irrigation and drying temperature was reported.