The effect of milling is investigated on structural changes in a physical mixture of CuO and Cr2O3 (denoted as CuO/Cr2O3), which is used as an active catalyst component for the low-temperature methanol synthesis via methyl formate. Detailed characterization of CuO/Cr2O3 by different techniques such as N-2 adsorption, X-ray diffraction (XRD), high-resolution transmission electron microscopy with elemental analysis (HRTEM/EDX) and X-ray absorption fine structure (XAFS) reveals that long-term milling causes intimate contact between fine grains of CuO and Cr2O3 and lattice disorder in CuO crystallites. No formation of any new compounds or solid solutions from CuO and Cr2O3 is ascertained in milled CnO/Cr2O3. The results suggest that both effects, i.e., increased interfaces between CuO and Cr2O3 and enlarged lattice disorder in CuO, contribute to the enhanced catalytic performance for the methanol synthesis. The combined results of HRTEM and XAFS analysis show that the crystallographic disorder proceeded on the edges of CuO grains.