Background : Ginseng root rot is a devastating disease caused by the fungus, Ilyonectria mors-panacis that generally attacks younger roots (-2 years), leading to defects in root quality, ginsenoside accumulation and also life cycle of the plant. Hence, there is an indispensable need to develop strategies resulting in tolerance against ginseng root rot. The protective role of silicon during pathogen infestation is well documented in other plant systems and a previous study demonstrated that silica nanoparticles are absorbed and accumulated more than the bulk silica in maize. However, the role of silica in ginseng-root rot pathosystem is unknown. Methods and Results : In the present study, we evaluated the effect of silica nanoparticles (N-SiO2) in Panax ginseng during I. mors-panacis infection. Long term analysis (30 dpi) revealed a striking 50% reduction in disease severity index upon 1 mM and 2 mM treatment of N-SiO2. However, N-SiO2 did not have any direct antifungal activity against I. mors-panacis. Candidate genes and metabolites based approach revealed jasmonic acid (JA) mediated sterol accumulation and incresed ginsenside biosyntesis as the key transcriptional reprogramming events orchestrated by N-SiO2 during the fungal infection. Conclusion : In a nut shell, N-SiO2 administration induces transcriptional reprogramming in ginseng roots, leading to increased phytosterol and ginsenosides synthesis resulting in enhanced tolerance against I. mors-panacis.