The rhizome of Polygonatum sibiricum is a traditional Chinese medicine material and also a popular functional food consumed in China. Due to the increasing demand and overexploitation, the use of the cultivated plant is growing rapidly. However, the difference in phytochemical profile and health benefit between the cultivated and wild-grown P. sibiricum has not been revealed yet. The objectives of this study are to compare the phytochemical profiles of two types of P. sibiricum, i.e., the cultivated and the wild-grown types, by using UHPLC-Q-Orbitrap-MS based untargeted metabolomics approach. We tentatively identified 190 phytochemicals belonging to alkaloids, flavonoids, phenolic acids, and terpenoids from both two types of samples. In general, there is distinctive difference in phytochemical profiles between these two types of samples. Specifically, 33 phytochemicals showed significant differences. Of these phytochemicals, 22 compounds, such as laetanine, p-coumaroyl-beta-D-glucose, geniposide, medicagenic acid, were significantly higher in cultivated type; 11 compounds, such as vicenin-2, kaempferol 7-neohesperidoside, vanillic acid, and obacunone, were significantly higher in wild-grown type samples. This study will expand our knowledge regarding the cultivated of P. sibiricum and facilitate its further application in pharmaceutical and food industries.