Differential adsorption of surfactants (e.g., collectors and depressants) on the minerals plays a key role in mineral flotation through selectively altering the surface wettability of minerals. In this study, to improve the removal efficiency of dolomite from apatite by direct flotation, hydrolytic polymaleic anhydride (HPMA) was introduced as an eco-friendly depressant for dolomite. The depressing performance and adsorption mechanism of HPMA on the dolomite and apatite surfaces were studied through flotation tests and surface analyses. Flotation results demonstrated that HPMA displayed an intense depressing impact on the dolomite flotation while affected slightly the apatite flotation. Surface wettability analysis indicated that the selective adsorption of HPMA at the dolomite/water interface declined significantly the dolomite hydrophobicity even in the case of sodium oleate (NaOl). Surface adsorption detection and zeta-potential results demonstrated that HPMA had a much stronger interaction with dolomite than apatite, resulting in the intense adsorption of HPMA onto dolomite. Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) further evidenced that compared with apatite, the strong interaction between HPMA and magnesium sites of dolomite enhanced the chemisorption of HPMA onto dolomite surface, which prevented strongly NaOl adsorption onto dolomite. As a result, dolomite was strongly depressed by HPMA to achieve the effective recovery of apatite. Based on these findings, HPMA can be potentially utilized as an eco-friendly and high-selectivity depressant for removing dolomite from apatite.