Lenzites betulina has been recognized as a rich source of chemical components, including polysaccharides, sterides and sugar alcohols. In this study, cellulase−ultrasonic synergistic extraction method was applied to extract polysaccharides from L. betulina, and the response surface methodology was used to optimize the extraction conditions. The eight basic factors affecting extraction yield were evaluated by Plackett−Burman design (PBD). Then, the four important factors significantly affecting the yield of polysaccharides from L. betulina, including enzymolysis temperature, enzymolysis time, ultrasound time and ultrasound temperature, were optimized by Box−Behnken design (BBD). Maximum extraction yield of L. betulina polysaccharides was 13.64±0.09 % at a cellulase dosage of 0.8 %, enzymolysis temperature of 60 °C, enzymolysis time of 180 min, pH of 4.5, liquid‐solid ratio of 45 ml/g, ultrasound power of 300 W, ultrasound time of 20 min and ultrasound temperature of 45 °C. Subsequently, the characteristic structure of crude polysaccharides was determined by FT‐IR. Results indicated that cellulase−ultrasonic synergistic treatment is suitable for L. betulina polysaccharides extraction, and it has good prospect for development and utilization.