As an emerging desalination technology for hypersaline wastewater treatment, membrane distillation (MD) faces a critical challenge of membrane wetting. The state-of-the-art wetting mitigation strategy in MD is to use novel membranes that are commercially unavailable and difficult to fabricate. This study proposes an operational mode, negative pressure MD (NPMD), as a novel wetting mitigation strategy in MD operations. Compared with conventional MD, NPMD can substantially enhance the wetting resistance of commercially available hydrophobic MD membranes. Specifically, in a conventional direct contact MD (DCMD) operation, a polyvinylidene fluoride (PVDF) membrane is easily wetted by a 0.1 mM sodium dodecyl sulfate (SDS) feed solution, while in NPMD, the PVDF membrane can remain unwetted with a 0.2 mM feed solution. By determining the liquid entry pressure (LEP) of the PVDF membrane using an impedance-based technique, the working mechanism of NPMD for wetting mitigation is illustrated, and such a mechanism is further confirmed by DCMD experiments using feed solutions containing ethanol. With a negative gauge pressure on the feed stream, the transmembrane hydraulic pressure becomes lower than the LEP of the PVDF membrane, thereby mitigating membrane wetting. As a simple yet effective wetting mitigation strategy, NPMD can be readily implemented in practice with commercially available hydrophobic membranes, showing vast potential to advance MD applications.