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• The metabolomics and proteomics of CSF exhibit significant disparities between neuro-PASC patients and healthy volunteers. • Elevated sphinganine and ST1A1, disrupted sphingolipid metabolism and attenuated inflammatory response may lead to neuro-PASC. • Decreased 7,8-dihydropterin and upregulated steroid hormone biosynthesis may be a reparative mechanism for neuro-PASC. • Biomarker cohort consisting of sphinganine, 7,8-dihydroneopterin, and ST1A1 shows promising efficacy in diagnosing neuro-PASC. The mechanism by which SARS-CoV-2 causes neurological post-acute sequelae of SARS-CoV-2 (neuro-PASC) remains unclear. Herein, we conducted proteomic and metabolomic analyses of cerebrospinal fluid (CSF) samples from 21 neuro-PASC patients, 45 healthy volunteers, and 26 inflammatory neurological diseases patients. Our data showed 69 differentially expressed metabolites and six differentially expressed proteins between neuro-PASC patients and healthy individuals. Elevated sphinganine and ST1A1, sphingolipid metabolism disorder, and attenuated inflammatory responses may contribute to the occurrence of neuro-PASC, whereas decreased levels of 7,8-dihydropterin and activation of steroid hormone biosynthesis may play a role in the repair process. Additionally, a biomarker cohort consisting of sphinganine, 7,8-dihydroneopterin, and ST1A1 was preliminarily demonstrated to have high value in diagnosing neuro-PASC. In summary, our study represents the first attempt to integrate the diagnostic benefits of CSF with the methodological advantages of multi-omics, thereby offering valuable insights into the pathogenesis of neuro-PASC and facilitating the work of neuroscientists in disclosing different neurological dimensions associated with COVID-19. [ABSTRACT FROM AUTHOR]