In this study, the interaction of calcium, magnesium, and sodium as well as impact of monovalent to divalent (M/D) cation ratio and magnesium to calcium (Mg/Ca) ratio in the feed wastewater on membrane fouling in submerged membrane bioreactor (MBR) was investigated. The protein and carbohydrate content of soluble microbial products (SMP) and extracellular polymeric substances (EPS) as well as their relative hydrophobicities was examined. The mixed liquor and its components (soluble and suspended solids) were analyzed for their filtration resistance, as reflected by the modified fouling index (MFI). Based on the findings of this study, the optimum conditions with respect to fouling rate were calcium and sodium concentrations of 36 and 140 mg/L, respectively, M/D of 1:1 and Mg/Ca of 5:1, with all parameters on an equivalent basis. High sodium concentration at high M/D ratio was found to decrease the floc size and increase the fouling rate. At the low M/D ratio of 1:1, introduction of magnesium was beneficial in reducing the fouling rate by increasing the EPS concentration and floc size and decreasing the SMP concentration and relative hydrophobicity in the supernatant. The fouling rate was found to be statistically correlated with the concentrations of Ca, Mg, and Na, with both Ca and Na adversely impacting fouling and Mg alleviating fouling propensity.