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Background: Short-chain fatty acids (SCFAs) support mucosal integrity and reduce inflammation, while nesfatin-1 is a neuropeptide with antiapoptotic, anti-inflammatory, antioxidant, and anorexigenic actions. Their roles in inflammatory bowel disease (IBD) and links to quality of life (QoL) are unclear. Methods: We conducted a cross-sectional study including adults with Crohn’s disease (CD), ulcerative colitis (UC), and healthy controls (HC). Serum total short-chain fatty acids and nesfatin-1 were measured using enzyme-linked immunosorbent assays (ELISA). Quality of life was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). Group comparisons and correlation analyses were performed using non-parametric statistical methods. Results: Serum total SCFA concentrations did not differ significantly between patients with CD, UC, and HC (p = 0.29). Nesfatin-1 levels showed between-group variability, with lower values in CD compared with healthy controls, while patients with UC showed intermediate and variable levels (p = 0.064). An inverse correlation between SCFAs and nesfatin-1 was observed in UC and in the combined IBD cohort, but not in CD. Quality of life was comparably impaired in CD and UC. No statistically significant associations were observed between serum SCFAs or nesfatin-1 and IBDQ scores. Conclusions: In this pilot exploratory study, circulating SCFAs and nesfatin-1 showed distinct patterns across IBD subtypes, with evidence of subtype-specific associations between these biomarkers. However, no relationship with quality of life was demonstrated. Larger longitudinal studies are required to confirm these findings and clarify their clinical relevance.