Pyrophyllite is the most common hydrophobic mineral encountered in Fengshan iron sulfide ore, China. Commonly depressants for separation of pyrophyllite suffer the disadvantages of limited availability and high cost. To solve this problem, a novel polysaccharide xanthan gum (XGM) was proposed for the suppression of pyrophyllite. The flotation response and depression mechanism were examined by flotation tests, adsorption and Fourier transform infrared spectra (FTIR), and molecular dynamics simulation (MDS) as well as scanning electron microscopy (SEM) and energy dispersive X-ray spectrometry (EDS). The flotation and adsorption tests showed that the floatability of pyrophyllite became weaker after adding the polysaccharide XGM compared with the conventional depressant guar gum (GG) and carboxymethyl cellulose (CMC). Meanwhile, the greater adsorption amount of XGM on the pyrophyllite surface was obtained than that of GG and CMC. Fourier transform infrared spectra, scanning electron microscope and molecular dynamics simulation were conducted to reveal the depression mechanism. The XGM molecule preferred to pyrophyllite surface, and anionic XGM strongly absorbed on pyrophyllite (1 0 0), (0 1 0) surfaces by 000 groups in its molecular structure. After treating with XGM, the oxygen atom was enriched and sodium atom was found on the pyrophyllite surface, which caused a strong chemisorption between XGM and pyrophyllite. On the whole, the polysaccharide XGM is an excellent depressant for pyrophyllite suppression.