Membrane distillation (MD) is a promising technique for desalinating hypersaline brine, such as produced water (PW). To date, fouling and scaling have remained as major challenges for MD implementation. In this study, chlorine dioxide combined with induced air floatation (ClO2-IAF) was systematically investigated as a pretreatment prior to MD. First, the ClO2 generation based on sodium chlorite and hydrochloric acid was optimized to maximize the on-demand ClO2 production. The maximum production yield of 18.4% was obtained with 4 wt.% NaClO2 and 20 wt.% HCl solutions, with a molar ratio of 1:1.25. Then, two real PW samples were pretreated, and removal efficiencies for total suspended solids (TSS), turbidity, iron, and total organic carbon (TOC) were comprehensively studied by varying the ClO2 dosage between 6 and 91 mg/L. The ClO2-IAF pretreatment displayed TSS and turbidity removals above 90% and TOC removal close to 55%. The PW constituents such as benzene, toluene, ethylbenzene, xylene (BTEX), and total petroleum hydrocarbons (TPH) were analyzed and quantified throughout the cascade of the treatments. The volatiles like BTEX were mainly removed by air floatation, while saturated hydrocarbons such as TPH were retained by the hydrophobic membrane. The MD long-term stability without any in-place cleaning was evaluated, and the membrane withstood for twenty two days without wetting, suggesting that optimizing oxidation pretreatment is critical for mitigating the fouling in MD. Results suggest that organic fouling in PW could be effectively reduced by the pretreatment, but further treatment is required to mitigate the scaling, which resulted in MD wetting.