Poria cocos Wolf is a popular traditional medicinal plant that has invigorating activity. Water-soluble polysaccharides (PCPs) are its main active components. In this study, four different methods were used to extract PCPs, which include hot water extraction (PCP-H), ultrasonic-assisted extraction (PCP-U), enzyme-assisted extraction (PCP-E) and microwave-assisted extraction (PCP-M). Their chemical compositions and structure characterizations were compared. In vitro antioxidant activities were studied on the basis of DPPH radical, hydroxyl radical, reducing power and metal chelating ability. The results showed that PCPs were composed of mannose, glucose, galactose, and arabinose, and had typical IR spectra characteristics of polysaccharides. Compared with other PCPs, PCP-M had lower neutral sugar content, higher mannose content and higher uronic acid content. The molecular weight were determined as PCP-E < PCP-M < PCP-U < PCP-H. PCP-M showed the strongest reducing power and highest scavenging abilities on hydroxyl and DPPH radicals, while PCP-U exhibited the lowest antioxidant activities. Response surface methodology was used to optimize the extraction yield of PCP-M by implementing the Box–Behnken design. Under the optimized conditions, the PCP-M yield was 9.95%, which was well in close agreement with the value predicted by the model. Overall, the microwave-assisted extraction was an effective and mild method for obtaining antioxidant polysaccharides from P. cocos Wolf.