•Isotropic polyethersulfone (PES) membrane was successfully developed via the vapor-induced phase separation (VIPS) method.•The isotropic PES membrane demonstrated outstanding underwater superoleophobicity (OCA of crude oil, 145 ± 2.0) and oil-repellency properties.•The isotropic PES membrane has superior water permeability of 4721 L/h⋅m2⋅bar that is about 13.6 times higher than that recorded by anisotropic PES.•The isotropic PES membrane showed excellent oil-in-water emulsion separation efficiency (>98%) for different heavy oil concentrations.•The isotropic PES membrane showed durable oil-fouling repellency, which could be easily recycled with a flux a recovery ratio of 59.5% over three subsequent cycles. Isotropic polyethersulfone (PES) membrane for separation of oil-in-water nanoemulsion was successfully developed using non-solvent vapor-induced phase separation (VIPS). The surface and structural properties of the fabricated PES membranes were thoroughly characterized using various techniques. The membrane separation performance was evaluated in terms of permeate flux, oil rejection, antifouling capability, and water flux recovery. Remarkably improved surface hydrophilicity for isotropic PES membrane (contact angle, CA = 39°) compared to anisotropic PES membrane (CA = 70°), resulting in superior pure water permeance, attaining 4721 L/h⋅m2⋅bar at operating pressure of 0.5 bar. The isotropic PES membrane achieved superior crude oil-in-water nanoemulsion separation (permeance of 713 L/h⋅m2⋅bar and 100% rejection) at oil concentration of 1 g/L. At extremely high oil concentration of 50 g/L, the PES membrane was not completely fouled and showed permeance of 65 L/h⋅m2⋅bar and 98.2% rejection. Moreover, the flux recovery of the fouled isotropic PES membrane exceeded 59.5% over three subsequent cycles of filtration and back-washing with water. Overall, this study might provide substantial guidance for large-scale manufacturing and application of isotropic PES membrane in treating practically challenging emulsified oil-in-water nanoemulsion under harsh conditions.