Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) that primarily affects the small intestine. Patients undergoing surgery provided blood and tissue samples for subsequent molecular profiling, including data-dependent and data-independent proteomics, data-dependent oxylipin analysis and data-independent metabolomics. Comparison of inflamed tissue samples with less inflamed matched controls revealed a significant loss of antimicrobial proteins, mitochondrial proteins, xenobiotic enzymes and enzymes involved in lipid metabolism in diseased tissue samples. Inflammation-related proteins, platelet-derived proteins and protein markers of hypoxia were found to be upregulated. These findings were corroborated by characteristic patterns of proteins, oxylipins and metabolites detected in blood serum and related to inflammation, platelet activation and hypoxic stress. The present data suggest a synergistic escalation of events involved in mitochondrial function, detoxification, gut microbiome control and blood coagulation, and may allow better prediction of disease risk factors.