Aimed to comprehensively investigate the presence of neural autoantibodies in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients experiencing neurological complications during the Omicron wave in China. Forty consecutive COVID-19 patients with severe neurological complications and 15 disease controls (DC) were enrolled in the study. Neural autoantibodies were detected using both the indirect immunofluorescence assay (IFA) on mouse brain tissue and the Brain-neuronal-antigen microarray. A bioinformatics analysis was conducted to evaluate the similarity between SARS-CoV-2 proteins and the specific antigens identified by the microarray. Our results showed a markedly elevated prevalence of neural autoantibodies in CSF (62.16% vs. 0.0%) and in plasma of COVID-19 patients compared to DC using IFA. Additionally, we identified 12 upregulated intrathecal IgG autoantibodies with differential levels between COVID-19 patients and DC, as well as 51 upregulated IgG autoantibodies in plasma. Anti-mGluR2 antibodies exhibited the highest positivity rate in COVID-19 patients, a finding further confirmed by cell-based assays (CBA). Moreover, we discovered a shared peptide similarity between the SARS-CoV-2 N, S protein and mGluR2. Among two COVID-19 patients with positive anti-mGluR2 antibodies, there were specific and prominent bindings to both the RBD-Fc of S and mGluR2, while only weak binding was observed to N.