Gasdermins (GSDMs) are a family of pore forming proteins, that play a crucial role in various biological processes such as immune response, and have been associated with cancers, autoimmune diseases and other disorders. They are essential executors of pyroptosis, a lytic type of inflammatory cell death. Several cellular stressors such as bacterial infections, ionic imbalance, and toxins cause GSDM activation, allowing these proteins to form large membrane pores, cytokine release, and cell death. However, little is known about how these proteins are regulated and their cell specific functions. Here, we identify the ubiquitin ligase NEDD4L as a key regulator of GSDMD and GSDME, two GSDMs involved in cell death. NEDD4L interacts with and ubiquitinates both these proteins to control their stability and intracellular expression levels. Knockout of mouse Nedd4l (Nedd4-2) results in lung and kidney damage with perinatal lethality within three weeks of birth. These mice demonstrated elevated GSDMD in alveolar epithelia and increased GSDME in kidney tubular epithelia, suggesting tissue specific regulation by NEDD4L. Kidney specific Nedd4l knockout mice showed GSDMD and GSDME activation, tubular cell death and reduced kidney function after high sodium diet. NEDD4L-deficient cells were significantly more susceptible to GSDM activation and showed higher IL-1β release and increased cell death induced by NLRP3 agonists, cytotoxic agents and bacterial infection. These results demonstrate that NEDD4L regulates GSDMD and GSDME functions by preventing their accumulation and reveals an unexplored link between GSDM stability and cell death, which is distinct from current GSDM inhibitors that prevent membrane targeting.