Mitochondrial dysfunction is increasingly recognized as a shared feature of Alzheimer's disease (AD) and inflammatory bowel disease (IBD), linked through overlapping pathways of hypoxia and immune dysregulation. Our study integrated transcriptomic and genetic analyses to uncover mitochondria-related mechanisms underlying these diseases. By analyzing multiple AD and IBD datasets through differential expression gene (DEG) analyses, biological pathway enrichment, and co-expression module construction, we identified hypoxia-induced mitochondrial dysfunction as a central risk factor for both conditions. Key findings revealed several mitochondrial-related genes shared between AD and IBD, including BCL6, PFKFB3, NDUFS3, and COX5B, which serve as critical regulators bridging mitochondrial and immune pathways. Drug enrichment analyses using Drug Signatures Database (DsigDB) and the Connectivity Map (cMAP) identified promising therapeutic candidates, including decitabine, DMOG, and estradiol, targeting shared regulators such as BCL6, PFKFB3, MAFF, and TGFBI. These drugs demonstrated potential to modulate mitochondrial autophagy and oxidative phosphorylation (OXPHOS), pathways enriched in the constructed interaction network with BCL6 and PFKFB3 as central nodes. Mendelian randomization (MR) analysis further identified MAP1LC3A as significantly associated with increased risk for both AD and IBD, while NME1 emerged as strongly protective, suggesting their roles as therapeutic targets. Our findings underscore hypoxia-induced mitochondrial dysfunction as a unifying mechanism in AD and IBD, mediated by hypoxia-inducible factor-1α (HIF-1α). By identifying key mitochondria-associated genes and pathways, this study highlights innovative therapeutic targets and contributes to a deeper understanding of the gut-brain interplay in neurodegeneration and chronic inflammation. These insights pave the way for precision medicine strategies targeting mitochondrial dysfunction in AD and IBD.