This study aimed to identify hub genes and pathological mechanisms related to neuroinflammation in Sporadic Creutzfeldt-Jakob disease (SCJD) based on comprehensive bioinformatics. SCJD and normal samples were collected from GSE160208. Weighted gene co-expression network analysis (WGCNA) and Limma R package were used to obtain key genes, which were used for enrichment and immune cell infiltration analyses. Protein-protein interaction (PPI) network, cytoHubba, and machine learning were used to screen the central genes of SCJD. The chemicals related to hub genes were predicted and explored by molecular docking. 88 candidate genes were screened. Enrichment analysis showed they were mainly related to bacterial and viral infection and immune cell activation. Immune cell infiltration analysis suggested that immune cell activation and altered activity of the immune system are involved in the progression of SCJD. After identifying hub genes, KIT and SPP1 had higher diagnostic efficacy for SCJD (AUC > 0.9), so they were identified as central genes. The molecular docking results showed hub genes both docked well with Tretinoin. KIT, SPP1, and Tretinoin are essential in developing neuroinflammation in SCJD and may provide new ideas for diagnosing and treating SCJD.