Background: Silybum marianum, a member of the Aster family, is a well-known Chinese herb and the source of a popular antioxidant that is extensively used in Asia. The abundant S. marianum straws are still underutilized and wastefully discarded to pollute the environment. Objective: To solve the above problem and better utilize S. marianum straws, the objective of this study was to optimize the conditions for extraction of silymarin from S. marianum straws. Materials and Methods: A combination of microwave-assisted extraction and response surface methodology (RSM) was used for silymarin from S. marianum straws and yield assessment by high-performance liquid chromatography method. The RSM was based on a five-level, four-variable central composite design (CCD). Results: The results indicated that the optimal conditions to obtain highest yields of silymarin were microwave power of 146 W, extraction time of 117 s, liquid-to-solid ratio of 16:1 mL/g, and ethanol concentration of 43% (v/v). Validation tests indicated that under the optimized conditions, the actual yield of silymarin was 6.83 ± 0.57 mg/g with relative standard deviation of 0.92% (n = 5), which was in good agreement with the predicted yield. Conclusions: The exploitation of the natural plant resources present very important impact for the economic development. The knowledge obtained from this work should be useful to further exploit and apply this material.