Diosgenin, a hydrolysis product from Dioscorea plants, can be used as a precursor of steroid drugs (e.g., progesterone, testosterone, and glucocorticoid). However, traditional acid hydrolysis production wastes water and causes severe environmental pollution. The extraction of diosgenin through microbial transformation is the most green and environmentally friendly method at present. In order to improve the efficiency of the extraction of diosgenin through microbial transformation, we proposed a new method of strain mutagenesis. After mutagenesis, the response surface methodology was used to optimize the solid-state fermentation medium, thereby improving the diosgenin yield. We found that the optimal formulation was 5.5% sucrose, 0.6% NH4H2PO4, and 26.6% wheat bran. The final extraction rate of diosgenin reached 0.439% (the value of diosgenin per g. of starting plant dry material). Compared with 0.338% before optimization, it had increased 1.29 times. Furthermore, two other compounds were isolated from the fermentation products. These were identified as diosgenone (C27H41O3) and yuccagenone (C27H42O3). Traditional diosgenone is obtained through the oxidation of diosgenin with oxalic acid, but the method in this study is directly obtained from Dioscorea rhizome powder. The price of Dioscorea rhizome powder is much lower than diosgenin, thus greatly reducing the cost of obtaining diosgenone. This method provides a basis for subsequent research on other pharmacological compounds.