Zinc (Zn) is an essential nutrient for plants and is required for normal growth and metabolism. Many enzymes involved in primary metabolism like respiration, photosynthesis, and biosynthesis of plant hormones, possess Zn as a cofactor for their moiety. Zn at elevated concentrations in soil has hazardous effects on plants and leads to retarded cell division and elongation, affects growth and biomass production, impairs photosynthesis, and is often linked with oxidative stress by inducing reactive oxygen species (ROS). Andrographis paniculata is one of the popular medicinal herbs in Asia. It serves a pivotal role in Ayurveda as a traditional medicine and a source of anti-cancerous drug andrographolide (AG). The current study focused on exploring the enhancement of AG content within the plant under zinc stress. The study highlights the impact of various concentrations of Zn (50, 100, and 150 mg kg−1) as zinc sulphate (ZnSO4 × 7H2O) on plant health, antioxidative enzymes and elicitation of AG biosynthesis in A. paniculata in a pot experiment with sandy loam soil in the greenhouse. Growth attributes such as plant height and fresh and dry biomass of seedlings were reduced with consistent increases in concentrations of Zn. The activities of enzymes such as catalase, guaiacol peroxidase, peroxidase, ascorbate peroxidase, and glutathione reductase rose with increasing concentrations of Zn. The maximum applied concentration (150 mg Zn kg−1) showed the maximum activity of all studied antioxidative enzymes. Elevated zinc concentrations in soil correlate with increased total phenolic content, MDA content, electrolytic leakage, and H2O2 levels in A. paniculata. As the Zn content in soil increased, the AG contents in A. paniculata leaves increased and was maximum recorded at 150 mg kg−1 of Zn. The Zn levels in root and shoot demonstrated a marked linear correlation with the concentrations of Zn applied to the soil. Results suggest that A. paniculata confer Zn tolerance by modulating antioxidative enzymes and increased synthesis of AG. The present finding is the first report on Zn-mediated AG production in A. paniculata.