Penthorum chinense Pursh (PCP) is a kind of functional food or medicine for liver protection. In the present work, Plackett-Burman design, steepest ascent method, and response surface methodology (RSM) were employed to obtain maximum total sugar yield. The experimental yield of 6.91% indicated a close agreement with the predicted yield of 7.00% of the model under optimized conditions. The major polysaccharide fraction (PCPP-1a) from PCPP was purified and identified as acidic polysaccharides with a high content of uronic acid (FT-IR, UV, HPGPC). PCPP had similar monosaccharide profile with PCPP-1a but was rich in galacturonic acid (HPLC). Both of PCPP and PCPP-1a possessed strong hydroxyl radical scavenging, DPPH radical scavenging, and Fe2+ chelating activities. Moreover, they were revealed to show strong anti-inflammatory activities by inhibiting NO, TNF-α, and IL-1β release compared to LPS treatment in RAW264.7 cells. These data suggest that the polysaccharides from PCP could be potential natural products for treating ROS and inflammatory-related diseases.