Diabetic foot ulcers (DFUs) represent a growing global health concern and remain among the most challenging conditions in limb salvage. Negative pressure wound therapy (NPWT) has become an important adjunct in DFU management, improving wound healing rates, stimulating granulation tissue formation, and potentially reducing amputation risk when compared to standard wound care. This chapter reviews the clinical applications, mechanisms, and evidence supporting NPWT in the multidisciplinary management of complex lower extremity wounds. Current evidence suggests that NPWT enhances wound bed preparation, accelerates closure, and improves reconstructive outcomes across a spectrum of diabetic and vasculopathic wounds. Multiple randomized controlled trials and meta-analyses have shown superior healing rates and reduced time to closure relative to conventional dressing techniques, without a corresponding increase in adverse events. Current best practices and indications for NPWT use are summarized, including patient selection, wound preparation, and integration with other modalities in the limb salvage algorithm. The chapter also presents clinical pearls and pitfalls, addressing challenges such as seal failure, periwound maceration, and pressure injury related to tubing placement. Variant forms of NPWT, including NPWT with instillation (NPWTi) and the Waffle VAC, are discussed as evolving techniques designed to optimize infection control, exudate clearance, and wound conformability in complex or contaminated wounds. Future directions continue to focus on refining the role of NPWT within multidisciplinary care frameworks, establishing standardized protocols across wound subtypes, and identifying patient- and wound-specific predictors of treatment success. Ongoing investigation into optimal instillation solutions, pressure settings, and cost-effectiveness will further define the contribution of NPWT to durable wound closure and long-term limb preservation.