Lead (Pb) exposure induces oxidative stress in plants, altering the biosynthesis pathways to produce specialized metabolites. This strategy contributes to plants' ability to relieve Pb-induced oxidative stress. This study investigates the role of secondary metabolites, with particular emphasis on phenylethanoid glycosides (PhGs), i.e., acteoside and echinacoside, to counterattack Pb-induced oxidative stress in Scrophularia striata Boiss. To investigate the impact of Pb exposure on the biosynthesis of metabolites in the phenylpropanoid pathway, plants were subjected to 250 mg L−1 Pb (NO3)2 for 24, 48, and 72 h in a hydroponic culture system. Stimulation of total phenolic, flavonoid, and flavonol production by Pb treatment was associated with up-regulation of phenylalanine ammonia-lyase (PAL), coumarate CoA ligase (4CL), and p-coumarate 3-hydroxylase (C3H) genes. The profile of phenolic compounds changed in response to Pb exposure compared to the control, depending on organs and time exposure. The increased expression levels of the 4CL gene are associated with a decrease in its substrates, i.e., caffeic, ferulic, and sinapic acids. These phenolic acids are the precursors of more complex end products. Rosmarinic acid showed a significant decrease in plants under Pb stress compared to untreated plants. The concentration of acteoside and echinacoside increased at all treatment times. Compound profiles changed toward metabolites with higher antioxidant activity. The production of PhGs, particularly acteoside with higher antioxidant activity, increased compared with the other metabolites in response to Pb stress. This study showed that S. striata adjusts the phenylpropanoid pathway toward increasing the antioxidant power of the plant and tries to reduce the Pb-induced oxidative stress.