The Pb-Zn metallogenic district in NW Guizhou Province is an important part of the Yunnan-Sichuan-Guizhou Pb-Zn metallogenic province, and also is one of the most important Pb-Zn producers in China. The hosting rocks of the Pb-Zn deposits are Devonian to Permian carbonate rocks, and the basement rocks are meta-sedimentary and igneous rocks of the Proterozoic Kunyang and Huili groups. The ore minerals are composed of sphalerite, galena and pyrite, and the gangue minerals are include calcite and dolomite. Geology and C-O isotope of these deposits were studied in this paper. The results show that δ¹³C and δ¹⁸O values of hydrothermal calcite, altered wall rocks-dolostone, sedimentary calcite and hosting carbonate rocks range from −5.3‰ to −0.6 ‰ (mean −3.4‰) and +11.3‰ to +20.9 ‰ (mean +17.2‰), −3.0‰ to +0.9 ‰ (mean −1.3‰) and +17.0‰ to +20.8‰ (mean +19.7‰), +0.6‰ to +2.5 ‰ (mean +1.4‰) and +23.4‰ to +26.5 ‰ (mean +24.6‰), and −1.8‰ to +3.9‰ (mean +0.7‰) and +21.0‰ to +26.8‰ (mean +22.9‰), respectively, implying that CO₂ in the ore-forming fluids was mainly a result of dissolution of Devonian and Carboniferous carbonate rocks. However, it is difficult to evaluate the contribution of sediment de-hydroxylation. Based on the integrated analysis of geology, C and O isotopes, it is believed that the ore-forming fluids of these carbonate-hosted Pb-Zn deposits in this area were derived from multiple sources, including hosting carbonate rocks, Devonian to Permian sedimentary rocks and basement rocks (the Kunyang and Huili groups). Therefore, the fluids mixing is the main precipitation mechanism of the Pb-Zn deposit in this province.