To better control nanofiltration (NF) membrane fouling during mine water treatment, an accurate elaboration of the fouling mechanisms of anionic polyacrylamide (APAM) coexisted with Ca2+ and fulvic acid (FA) is vital. An attractive phenomenon was observed during the membrane fouling tests: When Ca2+ and FA coexist with APAM, increasing Ca2+ concentration at high Ca2+ concentration will alleviate membrane fouling. The degree of membrane fouling is determined by the interaction of the foulant with the membrane and is closely related to the Lewis acid-base (AB) interaction energy. At the shortest separation distance, the AB interaction energy decreased from 3608 kT to −17,386 kT when the Ca2+ concentration was increased from 0 mM to 2 mM, then increased to −14,385 kT when the Ca2+ concentration was further increased to 6 mM. The change in AB interaction energy explains the dynamic evolution of the membrane fouling phenomenon. This work elucidates the effects of high Ca2+ concentrations on organic fouling and will benefit the better understanding of the efficient NF processes when multiple pollutants coexist.