This work addressed the mechanochemical activation of chalcopyrite by vertically stirred ball milling (VSBM) to enhance copper dissolution in leaching. Grinding with Zr balls and quartz sand as dispersing agent produced a significant increase of copper extraction from +10% to +40%, depending on grinding conditions. X-ray diffraction (XRD) and x-ray absorption fine structure (XAFS) results highlighted that the mechanochemical activation of chalcopyrite occurred through partial oxidation and rupture of crystal lattice. The contribution of each activation mechanism to leaching enhancement was assessed by two-stage leaching. The 10% increase of copper extraction in first stage leaching by H2SO4 confirmed the increase of soluble copper due to mechanochemical oxidation. Second stage leaching by H2SO4-Fe-2(SO4)(3) highlighted a larger dissolution of copper from chalcopyrite and enhanced kinetics upon activation. Whether grinding by VSBM or not, the kinetics of second stage leaching was found to be controlled by ions diffusion through the solid product layer. The partial amorphization of chalcopyrite resulted into additional increase of copper extraction ranging from +6 to +11% and produced a decrease of leaching activation energy from 91.0 to 79.4 kJ/mol.