Alterations in lipid metabolism are a hallmark of cancer, with increased lipogenesis, fatty acid (FA) uptake, and lipid droplet accumulation emerging as defining features of many solid tumors. However, the role of lipid hydrolysis in cancer metabolism remains underexplored. To address this, we employed unbiased serine hydrolase-directed activity-based protein profiling of patient-derived lung tumors and adjacent normal tissue, combined with comprehensive proteomics and lipidomics analysis. Strikingly, several lipid hydrolases showed reduced activity and abundance in lung tumors, including monoglyceride lipase (MGL), epoxide hydrolase 1 (EPHX1), carboxylesterase 1 (CES1), neutral cholesterol ester hydrolase 1 (NCEH1), and patatin-like phospholipase domain-containing protein 6 (PNPLA6). Concomitantly, the lipid profile of tumors was altered, with many lipid species elevated. Triacylglycerols were especially enriched in tumors, particularly those containing long-chain and highly unsaturated FAs, suggesting lipid droplet accumulation. This was further supported by increased levels of the lipid droplet scaffolding protein Perilipin-2 (PLIN2), while ATGL - the main triacylglycerol hydrolase - was reduced in tumors, as confirmed by immunofluorescent staining. Lipid substrate assays of the downregulated hydrolases revealed that most possess monoacylglycerol (MG) hydrolysis activity, among others. Consistent with this, several MG species and the overall lipid class were more abundant in tumors, corroborating decreased monoacylglycerol hydrolysis in lung tumors. To investigate the functional consequences of reduced lipid hydrolase expression, we generated NSCLC cell lines stably overexpressing ATGL, MGL, EPHX1, CES1, NCEH1, or PNPLA6. Overexpression led to significantly reduced proliferation and extensive lipid remodeling, as shown by lipidomics analysis. This remodeling likely reflects cellular compensation for excess free FAs released upon heightened lipid hydrolysis, which must be re-esterified to prevent lipotoxic stress. In several cases, overexpression also reactivated FA β-oxidation, a pathway suppressed in tumors. Together, our findings indicate that reduced lipid hydrolase activity is a hallmark of NSCLC, contributing to a reprogrammed lipid metabolism geared toward storage rather than catabolism. This shift may help tumors mitigate oxidative stress and promote growth, while the restoration of lipid hydrolysis presents a potential metabolic vulnerability.