An efficient ultrasonic disruption extraction (UDE) of polysaccharides from Armillaria mellea (AM) were optimized by response surface methodology (RSM). Under optimum conditions: ultrasonic power 915.00 W, temperature 69.27 °C and time 39.13 min, the crude polysaccharides (AMPs) yield was 19.5%. Two purified fractions AMPs-1-1 and AMPs-2-1 were obtained through anion-exchange and gel chromatography. AMPs-1-1 was a heteropolysaccharide with average molecular weights of 1.23 × 10 Da, and composed of Glc, Gal and GlcA with mole percentages of 89.06%, 9.59% and 1.34%, respectively, owning a backbone structure of (1→)-β-d-Glcp, (1 → 3,6)-α-d-Glcp and (1 → 3)-β-d-Glcp residues. AMPs-2-1 was a heteropolysaccharide with average molecular weights of 6.76 × 10 Da, and composed of Glc, Gal, GlcA and Man with mole percentages of 65.28%, 22.87%, 2.87% and 8.98%, containing a main backbone chain of (1 → 3,6)-α-d-Glcp and (1 → 6)-β-d-Glcp residues. AMPs-2-1 possessed obviously antioxidant activities in terms of stronger scavenging activity against DPPH· and ABTS, higher FRAP and ORAC value than AMPs-1-1. AMPs-2-1 could promote splenocyte lymphocytes and RAW264.7 macrophages proliferation and enhanced the phagocytosis of macrophages, exhibited significant immunomodulatory activities. These results suggested that UAE is an effective extract technology, and AMPs-2-1 could be explored as potential natural antioxidants and immunomodulatory agents.