<p>Selenium (Se) enriched forest-grown ginseng is famous for its high Se content and excellent protein quality, which are necessary for varieties of metabolic processes and play an important role in both ginseng growth and its health benefits for humans. However, the regulatory mechanism underlying Se enrichment and molecular responses of forest-grown ginseng after application of exogenous Se is still unclear. This study investigated the effect of Se fertilizer on molecular changes in physiological metabolisms of forest-grown ginseng during the growth process by analyzing differentially expressed proteins (DEPs). The results showed that 371 proteins were significantly changed under application of Se fertilizer. Further KEGG pathway analysis indicated that the DEPs are primarily involved in carbon metabolism, biosynthesis of amino acids, protein processing in endoplasmic reticulum, phenylpropanoid biosynthesis, oxidative phosphorylation and spliceosome. The expression levels of ATP sulfurylase, adenosine 5’-phosphosulfate reductase, nitrate reductase, nitrite reductase, superoxide dismutase, catalase, and H⁺-ATPase were up-regulated in ginseng treated with Se, and these key DEPs were mainly related to the maintenance of cellular membrane, antioxidant capacity and resistance to stresses. These findings reveal the nutritional and functional differences and establish a theoretical basis for further research on protein biological functions in forest-grown ginseng.</p>