Mixtures of silica nanoparticles (SiO2 NPs) and natural organic matter (NOM) are ubiquitous in natural aquatic environments and pose risks to organisms. Ultrafiltration (UF) membranes can effectively remove SiO2 NP–NOM mixtures. However, the corresponding membrane fouling mechanisms, particularly under different solution conditions, have not yet been studied. In this work, the effect of solution chemistry on polyethersulfone (PES) UF membrane fouling caused by a SiO2 NP–NOM mixture was investigated at different pH levels, ionic strengths, and calcium concentrations. The corresponding membrane fouling mechanisms, i.e., Lifshitz–van der Waals (LW), electrostatic (EL), and acid–base (AB) interactions, were quantitatively evaluated using the extended Derjaguin–Landau–Verwey–Overbeek (xDLVO) theory. It was found that the extent of membrane fouling increased with decreasing pH, increasing ionic strength, and increasing calcium concentration. The attractive AB interaction between the clean/fouled membrane and foulant was the major fouling mechanism in both the initial adhesion and later cohesion stages, while the attractive LW and repulsive EL interactions were less important. The change of fouling potential with solution chemistry was negatively correlated with the calculated interaction energy, indicating that the UF membrane fouling behavior under different solution conditions can be effectively explained and predicted using the xDLVO theory.