The relationships between the structure of oxime compounds (R¹R²C=NOH, R¹/R²=alkyl groups) with different substituents and their corresponding flotation performances were studied. The analyses of density functional theory (DFT) calculations illustrated that the introduced phenyl group at the R¹ position could enhance the acidity, while the heptyl group could effectively increase the hydrophobicity and benefit van der Waals interactions. Meanwhile, the introduced amino group at the R² position could provide cationic sites to interact with negatively charged surfaces of minerals, while the introduced hydroxyl group could provide additional action sites to form stable chelates with metal ions. Based on the structure-activity relationships, structural optimization was carried out to obtain three efficient collectors, which possessed superior flotation separation performances, proving the effectiveness of the structural modification to oxime compounds in this work.