Abstract: To explore and expand new resources of Ganoderma lucidum polysaccharides, Ganoderma sessile was selected as the research object, given that it remains under-researched and rich in active ingredients with high contents. A microwave-assisted extraction method was adopted, with the polysaccharide content of Ganoderma sessile fruiting bodies serving as the evaluation index. Single-factor experiments were carried out to investigate the effects of five variables, including solid-to-liquid ratio, microwave power, extraction duration, extraction times and soaking time, on the extraction efficiency of Ganoderma polysaccharides. The Plackett–Burman experimental design was conducted to screen out three dominant influencing factors: Extraction time, soaking time and extraction times. On this basis, a three-factor and three-level regression model was established via Box–Behnken response surface methodology, so as to analyze the effects of key parameters on polysaccharide content and achieve systematic process optimization.With vitamin C solution set as the positive control, the in vitro antioxidant capacity of polysaccharides prepared under optimized conditions was evaluated. The antioxidant indicators involved total reducing power, as well as DPPH, ABTS and hydroxyl radical scavenging rates within a certain concentration range. The results showed that the optimal extraction conditions for polysaccharides from Ganoderma sessile fruiting bodies were as follows: Material-to-liquid ratio of 1:30 g/mL, microwave power of 325 W, extraction time of 9 min, soaking time of 30 min, and three extraction cycles. Under these conditions, the polysaccharide content reached 26.34%, which was consistent with the predicted value, with an RSD lower than 0.7%.The optimized extraction process for Ganoderma sessile polysaccharides features simple operation, favorable stability and excellent applicability. Meanwhile, the extracted polysaccharides presented potent in vitro antioxidant activity, which endows them with promising development and application prospects.