Abstract Membrane-based processes are increasingly applied in shale gas flowback and produced water (SGFPW) reuse. However, severe membrane fouling remains a big challenge for maintaining long-term operation. The present paper investigates for the first time the performance of the integrated ozonation-ultrafiltration (UF)-reverse osmosis (RO) process to treat SGFPW for water reuse. Results showed that pre-ozonation could efficiently mitigate membrane fouling. The integrated process removed more than 98% of total dissolved solids (TDS), 96% of dissolved organic carbon (DOC), and 96% of all ionic constituents in SGFPW. Significantly, the effluent could meet the water quality standards of irrigation, livestock water, and surface discharge. Removal of targeted pollutants is negatively influenced by the high concentrations of chloride and bromide because of their high reactivity with ozone and hydroxyl radicals (HO·). Through pre-ozonation, the total fouling index and the hydraulically irreversible fouling index decreased by more than 85% and 47%, respectively. The variation of particle sizes in SGFPW by pre-ozonation manifested the mechanism of UF membrane fouling mitigation, i.e., the pre-ozonation decomposed macromolecular organics into low fractions. The optimal ozone flow rate is 0.4 L/min. Results demonstrated that a sustainable SGFPW reuse could be achieved by the current integrated process.