Introduction Extending prior work where Low-Intensity Pulsed Ultrasound (LIPUS) enhanced systemic detection of miRNAs reflecting colonic mucosal status in murine colitis, this study investigates distinct molecules. We aim to identify LIPUS-enriched circulating metabolites that correlate with colonic mucosal inflammation, thereby expanding the repertoire of LIPUS-detectable biomarkers. Results Twenty eight-week-old female C57B/6N mice were randomly divided into healthy controls or an acute colitis group, induced by 7-day ad libitum 2.5% DSS in drinking water. On day 7, both groups received abdominal LIPUS (38 kHz, 150 mW/cm2, 180 s). Plasma, collected 2 h post-LIPUS, underwent LC-MS untargeted metabolomics. MSEA evaluated pathways. Plasma analysis revealed distinct LIPUS-enriched metabolite profiles between colitic and healthy mice. Colitic mice plasma post-LIPUS showed elevated microbiota-associated compounds (tryptophan, glutamate, riboflavin pathways) and PE family members (e.g., Lyso-PEs), reflecting intestinal mucosal inflammation. Conversely, LIPUS-treated healthy mice plasma exhibited nucleoside precursors (pyrimidine metabolism) and galacturonate (vitamin C synthesis), potentially related to intestinal mucosal homeostasis. Conclusion LIPUS selectively modulates metabolite release reflecting colonic inflammatory status, distinct from the general metabolic discharge of injured tissue. Despite current limitations (e.g., sample size, absence of human validation), this research highlights LIPUS's promise as a non-invasive tool for assessing gut inflammation. Future investigations will prioritize human validation, alongside exploring the circulating metabolome during the recovery phase to further validate identified metabolites. These steps are crucial to confirm initial findings and establish the clinical utility of LIPUS-induced metabolic signatures for monitoring disease activity and therapeutic response.