Dietary supplements are important to sustain an adequate level of antioxidants to balance reactive oxygen species (ROS) in vivo. Hericium erinaceus is one of the rare wood-rotting mushrooms with polysaccharides, which play antioxidant roles in multiple physiological systems of the organism. Can higher polysaccharide content yield higher antioxidant activity? The research on this is scarce. Therefore, the influence of extraction conditions on contents and antioxidant activities of polysaccharide from H. erinaceus was investigated by response surface methodology. Three main independent variables (extraction temperature, time, solid-liquid ratio) were taken into consideration. The extraction and the antioxidant activities were optimized using a Box-Behnken design. Interestingly, the effects of each factor were personalized. Extraction temperature was the dominant factor influencing the polysaccharide contents and antioxidant activities. In addition, the optimal condition to obtain the highest yield of polysaccharide was not in accord with the optimal condition to maximize the antioxidant activities. The effects of every extraction factor on antioxidant activities were various, probably because different components obtained under different extraction conditions had diverse antioxidant mechanisms. This study will help researchers to focus more on the effective components and their antioxidant abilities, rather than blindly pursue the yields of total polysaccharides.