Laryngeal cancer is a common head and neck malignant cancer type. However, effective biomarkers for diagnosis are lacking and pathogenesis is unclear. Lipidomics is a powerful tool for identifying biomarkers and explaining disease mechanisms. Hence, in this study, non-targeted lipidomics based on ultra-performance liquid chromatography-quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS) were applied to screen the differential lipid metabolites in serum and allowed for exploration of the remodeled lipid metabolism of laryngeal cancer, laryngeal benign tumor patients, and healthy crowds. Multivariate analysis and univariate analysis were combined to screen for differential lipid metabolites among the three groups. The results showed that, across a total of 57 lipid metabolic markers that were screened, the regulation of the lipid metabolism network occurred mainly in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) metabolism. Of note, the concentration levels of sphingolipids 42:2 (SM 42:2) and sphingolipids 42:3 (SM 42:3) correlated with laryngeal cancer progression and were both significantly different among the three groups. Both of them could be considered as potential biomarkers for diagnosis and indicators for monitoring the progression of laryngeal cancer. From the perspective of lipidomics, this study not only revealed the regulatory changes in the lipid metabolism network, but also provided a new possibility for screening biomarkers in laryngeal cancer.