In this study, the structure of Siraitia grosvenorii polysaccharides (SGPs) changed significantly after digestion. After 48 h of in vitro fecal fermentation, Mw decreased and the content of CR showed a trend of increasing and then decreasing. The monosaccharide composition (glucose) of SGPs showed a trend of decreasing and then stabilizing during fecal fermentation, indicating that SGPs were partially degraded during in vitro fermentation and significantly degraded and utilized by the human intestinal microbiota. In addition, SGPs fermentation for 48 h increased the production of SCFAs especially acetic acid, propionic acid, and butyric acid. Moreover, after in vitro digestion and enzymatic digestion, the in vitro hypoglycemic activity of SGPs remained relatively high afterward, albeit reduced. This study contributes to a better understanding of the potential digestion and enzymatic mechanisms of SGP, which is important for the future development of SGP as a functional food and drug.