BACKGROUND: Disorders of gut-brain interaction (DGBIs) constitute a global health challenge. Overlapping DGBIs amplify the clinical severity and have a profound impact on health-related quality of life (HRQoL) and somatization. Data on the prevalence and overlap of all individual DGBIs and their clinical ramifications remains limited. This study sought to elucidate these aspects within a northern Indian tertiary healthcare setting. METHODS: This prospective cross-sectional study enrolled patients meeting Rome IV criteria for DGBIs and healthy controls (HC). Participants underwent elaborative assessments, including socio-demographic profiling, HRQoL evaluation (PROMIS Global-10) and somatization quantification (PHQ-12). Statistical analyses compared prevalence rates, overlap patterns and associated clinical outcomes between various groups. RESULTS: Of the 2538 patients screened, 1044 (41.1%) with DGBIs (age 41.7 ± 12.6 years, 51.9% males) were enrolled; along with 1021 age and gender-matched HCs. Most common gastrointestinal region involved was gastroduodenal (49.9%), followed by bowel (39.7%) and esophageal (33.3%). Most common DGBIs were functional dyspepsia (FD; 44.4%), functional esophageal disorders (FEsD;32.4%), functional constipation (FC;18%), irritable bowel syndrome (IBS;16.1%). Overlapping DGBIs were present in 40.3% patients, with FD-FEsD (23.9%) and FD-FC(22.1%) and FD-IBS (52;12.4%) overlaps being the most common. Compared to HC, DGBI patients had significantly poorer HRQoL scores (19.1 ± 0.7 vs. 13.52 ± 3.39; p < 0.001) and significantly increased somatization scores (2.5 ± 1.7 vs. 18.5 ± 0.7; p < 0.001). Further, patients with overlapping DGBIs had significantly poorer HRQoL and significantly increased somatization scores compared to non-overlapping counterparts. CONCLUSIONS: This study provides novel data on the clinical burden and the entire spectrum of overlapping and non-overlapping DGBIs, while studying their impact on HRQoL and somatization. DGBI patients had significantly poorer HRQoL and heightened somatization compared to HCs; with further detriments observed in those with overlapping DGBIs. These findings emphasize the need for an integrated multidisciplinary approach for the evaluation of possible overlaps and for assessment of HRQoL in all patients with DGBIs to improve clinical outcomes.