Italian viper's bugloss (Echium italicum L.), a valuable plant of the Boraginaceae family, is considered an important source of biologically active compounds such as alkaloids, naphthalene, terpenoids, and phenolic compounds. Using natural fertilizers, particularly Ascophyllum nodosum extract (A. nodosum) offers many positive effects on plants while mitigating the impact of drought stress. For that point, the interaction of A. nodosum included four doses (0, 2, 4, and 6 % v/v) applied to the E.italicum plant under three levels of drought stress (100, 70, and 40 % field capacity, FC). Results indicated that fresh and dry weights of leaf and root, chlorophyll index, and leaf area, reduced with increased drought level. In contrast, relative water content (RWC), electrolyte leakage (EL), total soluble sugars (TSS), free proline content, and malondialdehyde (MDA) increased with enhanced drought level. The finding indicated that A. nodosum could mitigate the adverse effects of drought-stress conditions through increasing agronomic traits, photosynthetic pigments, RWC, free proline content, and TSS, and decreased MDA and EL. Furthermore, the application of A. nodosum extract enhanced key parameters, including total phenolic content (TPC), total flavonoid content (TFC), phenylalanine ammonia-lyase (PAL) activity, and the activities of ascorbate peroxidase (APX), guaiacol peroxidase (GPX), and catalase (CAT) in both roots and leaves of E. italicum, under both normal and drought conditions. The maximum DPPH scavenging activity in the leaves and roots occurred at a 4 % A. nodosum, resulting in increases of 44.93 and 21.22 %, respectively, compared with the control group, under 70 % FC. Similarly, the highest shikonin was achieved at 4 % A. nodosum, which increased by 26.38 % compared with the control group, under 70 % FC. The application of A. nodosum at 4 % concentration is identified as the most effective treatment for enhancing the performance of E. italicum under drought stress. In conclusion, the findings underscore the beneficial effects of A. nodosum on mitigating drought stress through increasing proline accumulation, antioxidant enzyme activity, and shikonin in E. italicum.