The efficient separation of chalcopyrite and arsenopyrite is significant for preventing and controlling arsenic pollution. Herein, sodium diisobutyl dithiophosphate (SDD) selectively improves chalcopyrite hydrophobicity to achieve copper and arsenic separation in low alkali. The flotation test results show that SDD is stronger than butyl xanthate and ethyl thiocarbamate regarding selective collection ability. SDD accurately separates chalcopyrite and arsenopyrite under low alkali conditions. Frontier orbit analysis shows that the feedback π and positive σ bonds between SDD and arsenopyrite surface are the weakest among the three collectors. Surface wettability, adsorption capacity, FTIR, XPS, and adsorption simulation calculations reveal more detailed collecting mechanisms. Analysis shows that SDD can selectively improve the hydrophobicity of the chalcopyrite surface. The above results were attributed to SDD breaking the CaOH+ adsorption barrier on the chalcopyrite surface. On the contrary, the interaction between SDD and arsenopyrite is weak, resulting in SDD being unable to break through the cover of CaOH+ on the surface of arsenopyrite.