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Hydrophobic membranes are very susceptible to pore wetting when they contact the feed water containing surfactants or low-surface-tension liquids in membrane distillation (MD). Avoiding direct contact between feed water and hydrophobic membrane pores is a potential strategy to control membrane pore wetting. In this study, we successfully fabricated a polyamide thin-film composite (TFC) Janus membrane through interfacial polymerization, with a hydrophobic microporous membrane as the substrate. The fabricated TFC Janus membrane showed a super antiwetting ability when treating the hypersaline water containing surfactants (>0.4 mM sodium dodecyl sulfate) or ethanol (>40% v/v). The optical coherence tomography (OCT) observation revealed that no liquid water was present at the distillate-facing side of the polyamide layer. Therefore, we ascribed the super antiwetting ability to the fact that the polyamide layer could prevent the feed liquid from directly contacting hydrophobic pores. The TFC Janus membrane could also avoid the wetting induced by gypsum scaling because the polyamide layer could act as a barrier to hinder the intrusion of gypsum crystals into hydrophobic pores. In addition to the antiwetting ability, the TFC Janus membrane showed 10–20% increases in vapor flux, despite the existence of a dense polyamide layer. Because interfacial polymerization is the most commonly used method for the fabrication of commercial TFC membranes, this study provides a facile and scalable method to fabricate membranes with robust antiwetting ability.