Background: Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This study set out to explore the serum molecular profiles (I) underlying the disease subtypes, in association with (II) elevated fecal calprotectin and (III) disease activity states, (IV) upon treatment escalation, and (V) in patients who needed treatment escalation. Methods: The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Following robust annotation, single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures. Results: In (I), chronic inflammation, phosphatidylcholines, and bile acid homeostasis disturbances underlined the differences between Crohn's disease (CD) and ulcerative colitis. For (II), fecal calprotectin was associated with elevation of inflammatory proteins and sphingomyelins (SM) and decrease in bile acids, amino acids, and triacylglycerols (TG). (III) Relative to patient remission, active disease state was characterized by decreased SMs and increased inflammatory proteins and TGs. In (IV), treatment escalation was associated with augmented levels of inflammatory response-related proteins and reduced levels of amino acids. Notably, TGs increased consistently in the post-treatment escalation group. Moreover, needed-treatment-escalation patients had down-regulated TGs in (V). They also showed increased SMs and decreased signaling receptor binding proteins. Integrative signatures captured the differences between groups of five scenarios through cross-validation procedures. NFASC was selected as a biomarker in 4 of 5 scenarios with consistently lower levels in CD, elevated-calprotectin, active-disease-state, and needed-treatment-escalation patients. NFASC also increased in the post-treatment escalation group. Conclusion: Disturbances in immune response, bile acid homeostasis, amino acids, and lipids alteration potentially underlie the clinically heterogeneous spectrum of IBD. NFASC and TGs hold promise as potential biomarkers for multi-purpose IBD management.