A selective organic depressant was investigated to promote the separation of scheelite from calcite and fluorite. 1-Hydroxyethylidene-1, 1-diphosphonicacid (HEDP) could efficiently reduce the recoveries of calcite and fluorite to less than 20%, while that of scheelite remained above 85%. The selective interaction mechanism was demonstrated via Zeta potential and X-ray photoelectron spectroscopy (XPS) analyses. The conceivable adsorption models of reagents on mineral surfaces were constructed to explain their adsorption mechanism. HEDP exhibited an excellent ability to selectively depress calcite and fluorite attributed to the intense adsorption on their surfaces, whereas its adsorption on scheelite surface was feeble. The technology feasibility of using HEDP to improve the scheelite flotation performance was verified through laboratory and industrial tests. The roughing grade was dramatically improved from 1.22% to 1.68%, and the product grade was enhanced from 24.66% to 28.26% with a noteworthy improvement of cleaning recovery by 6.93%, which would produce a considerable economic benefit.