The present study aimed to investigate the method of preparing extract by solid-state fermentation (SSF) of Stereum hirsutum mycelial substrate mixed with ginseng extracts (GE) and explored the changes of 6 water-soluble nutritional components (WSNC) and antioxidant capacity in the extract using a simulated gastrointestinal digestion model. The results showed that the substrates were endowed with numerous WSNC and antioxidants (total antioxidant capacity increased from 0.12 to 0.69 mmol TE/L) during the fermentation process. Compared to undigested samples (UDS), digested samples (DS) contained more WSNC and higher antioxidant activity. Furthermore, significant amounts of free amino acids (FAA) (increased from 844.97 ± 6.56 mg/L to 6715.21 ± 17.63 mg/L), and the minor ginsenoside 20 (S)-protopanaxadiol (PPD) were detected in the DS, which was not observed in the UDS. The findings demonstrate that extract prepared by SSF of S. hirsutum mycelial substrate mixed with GE can be used as potential functional food and antioxidant.