Interaction between alloy elements Cu and Cr on MnS inclusions was studied by Scanning Transmission Electron Microscope (STEM)/X-ray energy-dispersive spectrometer (EDS) and the first principles calculation method. Assuming that the enrichments of Cu and Cr play a key role on pitting corrosion of low alloy steel, STEM/EDS were used to observe the enrichments of Cu and Cr on MnS inclusions in this study. The first-principles calculation, which is based on density functional theory was used to investigate the segregation behavior of Cu and Cr in the Fe matrix and the adsorption behavior of Cu and Cr on MnS surface. The atomic structures, electronic and energetic properties of clean and Cu or Cr adsorbed MnS surface were calculated. The results showed that both Cu and Cr tend to segregate on the Fe (1 1 0) surface rather than solid dissolved in the Fe bulk. MnS (1 0 0) is the most stable surface amongst the low-index surfaces, and H (hollow) is the most stable adsorption site for both Cu and Cr. Coadsorption of Cu and Cr on MnS (1 0 0) surface was also studied. The results showed that Cu and Cr promote the adsorption of each other on MnS (1 0 0) surface. However, this interaction is effective only within a certain distance between them. Overall, these findings will be helpful to understand the mechanism of pitting corrosion induced by MnS.