Background & Aims: Fatigue is frequent and disabling in patients with inflammatory bowel diseases (IBD) but its mechanisms are poorly understood. We investigated alterations in fecal microbiomes and serum metabolomes and proteomes in patients with quiescent IBD, with vs without fatigue. Methods: We performed a prospective observational study of patients (44% women; mean age, 39.8 y) with clinically and endoscopically quiescent Crohn's disease (n = 106) or ulcerative colitis (n = 60) at a tertiary hospital, from March 2016 through December 2018. Fatigue was assessed using the functional assessment of chronic illness therapy-fatigue scoring system and defined as a score of 43 or less. We performed metabolomic analysis of serum samples using liquid chromatography-mass spectrometry methods and proteomic analysis using multiplex proximity extension assay (PEA) technology. Stool samples were obtained from 50 patients and analyzed by shotgun metagenomic sequencing on Illumina HiSeq platform. Results: Of the 166 study participants, 91 (55%) were fatigued. Serum samples from patients with fatigue (n = 59) did not have significant increases in levels of inflammatory cytokines compared with serum samples from nonfatigued patients (n = 72). We found a statistically significant difference in a cluster of 18 serum metabolites between patients with fatigue (n = 84) vs without fatigue (n = 72) (P = .033); serum samples from patients with fatigue had significant reductions in levels of methionine (P = .020), tryptophan (P = .042), proline (P = .017), and sarcosine (P = .047). Fecal samples from patients with fatigue had a less diverse gut microbiome, with significant reductions in butyrate-producing bacteria, including Faecalibacterium prausnitzii (P = .0002, q =.007) and Roseburia hominis (P = .0079, q = 0.105). This fatigue-like microbiome was associated with fatigue scales and correlated with progressive depletion of metabolites from serum samples. Conclusions: In an analysis of fecal and serum samples from 166 patients with IBD, we found alterations in serum metabolites and fecal microbes that were associated with fatigue.