Background and objective <p>Functional dyspepsia (FD) represents a common functional gastrointestinal disorder with pathogenic mechanisms involving gut-brain axis dysfunction and intestinal dysbiosis. Homovanillic acid (HVA), the terminal metabolite of dopamine, has been recently identified as being regulated by gut microbiota with consequent effects on neurological function. This study aimed to investigate whether post-eradication fecal homovanillic acid levels are associated with long-term symptom improvement and inflammatory marker changes in patients with <i>Helicobacter pylori</i>-associated functional dyspepsia, and to explore the potential mechanisms through gut microbiota analysis.</p> Methods <p>This prospective cohort study enrolled 326 <i>H. pylori</i>-positive FD patients between January 2023 and June 2025. All patients received standard eradication therapy. Fecal HVA concentrations were measured 8–10&#xa0;weeks post-eradication, and patients were stratified by the median value into high HVA (<i>n</i> = 163) and low HVA (<i>n</i> = 163) groups. The Gastrointestinal Symptom Rating Scale (GSRS) was employed to assess symptom changes at baseline, 2&#xa0;months, and 12&#xa0;months post-eradication. Serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α) were measured. Gut microbiota composition was analyzed through 16S rRNA sequencing at 12&#xa0;months post-eradication.</p> Results <p>The high HVA group demonstrated a significantly higher <i>H. pylori</i> eradication success rate compared to the low HVA group (92.6% vs 85.9%, <i>P</i> = 0.042). At 12&#xa0;months post-eradication, the sustained symptom improvement rate was 58.3% in the high HVA group, significantly exceeding the 38.0% observed in the low HVA group (<i>P</i> &lt; 0.001). The GSRS total score in the high HVA group decreased from baseline 26.8 ± 9.7 to 20.1 ± 8.3 at 12&#xa0;months (25.0% reduction), whereas the low HVA group showed a decline from 27.3 ± 10.2 to 23.6 ± 9.4 (13.6% reduction). Regarding inflammatory markers, the high HVA group exhibited reductions of 54.2%, 49.6%, 44.8%, and 51.9% for CRP, IL-6, IL-8, and TNF-α, respectively, all significantly greater than those in the low HVA group (29.4%, 26.5%, 22.5%, and 27.6%, all <i>P</i> &lt; 0.001). Fecal HVA concentration demonstrated negative correlations with the GSRS total score at 12&#xa0;months (<i>r</i> = −&#xa0;0.487) and inflammatory marker levels. The high HVA group displayed higher gut microbiota diversity at 12&#xa0;months post-eradication, with significantly increased abundances of butyrate-producing bacteria Faecalibacterium (8.7% vs 5.2%) and Roseburia (4.3% vs 2.6%). Multivariate analysis revealed that high HVA level (OR = 3.42, 95%CI 2.15–5.43) served as an independent predictor of sustained symptom improvement.</p> Conclusion <p>Post-eradication fecal homovanillic acid levels are strongly associated with long-term symptom improvement and anti-inflammatory responses in <i>H. pylori</i>-associated FD patients. Higher HVA levels measured 8–10&#xa0;weeks after eradication therapy reflect successful microbiota recovery and are associated with favorable clinical outcomes at 12&#xa0;months. These findings suggest that fecal HVA may serve as a prognostic biomarker for identifying patients who will achieve sustained therapeutic benefits following <i>H. pylori</i> eradication, potentially guiding post-treatment monitoring strategies and personalized interventions to optimize gut microbiota recovery..</p>