Diethyldithiocarbamate (DDTC) is employed in the sulfide ore flotation process due to its excellent collection performance. Herein, we investigated the interfacial adsorption behavior of DDTC on the four main mineral phases of high-sulfur residue: sulfur, pyrite, sphalerite, and lead sulfate. The adsorption behavior of DDTC and H2O, namely, the adsorption structure and the energy and electron localization function cross section, were explored using density function theory calculation. The results were helpful in constructing a coadsorption model of DDTC and H2O, which was validated by pure mineral flotation and characterization of Fourier transform infrared spectra. The coadsorption model indicated that the adsorption of DDTC on sulfur, sphalerite, and lead sulfate was weak with physical bonding, while its adsorption on pyrite was strong with chemical bonding. Practical bench-scale high-sulfur residue flotation was performed, and the result was different from that obtained from pure mineral flotation. Our developed model predictions and mineral fugacity pattern analysis were synergistically used to explain this difference. Overall, this work proposes for the first time a coadsorption model of DDTC and H2O and provides important insights into interfacial adsorption in high-sulfur residue flotation.