Background: Hormone replacement therapy (HRT) is a cornerstone treatment for menopausal symptoms, yet its impact on gastrointestinal health is not well defined—particularly in women who undergo premature menopause. Given estrogen’s role in modulating gastrointestinal physiology, this study evaluates whether HRT increases the risk of gastroesophageal reflux disease (GERD) and related esophageal pathology differently in women with premature menopause versus postmenopausal women. Methods: This retrospective observational study utilized TriNetX, a global federated health research network. Two cohorts of HRT users were created: (1) women ≥45 years with natural menopause (ICD-10 N95.1) and (2) women ≤45 years with premature menopause (ICD-10 E28.31, E28.310, E28.319). All patients had a diagnosis of HRT use (Z79.890). Exclusion criteria included prior diagnosis of GERD or esophageal malignancy. Propensity score matching adjusted for confounders including pregnancy-related diagnoses. Outcomes included new diagnoses of GERD, Barrett’s esophagus, esophageal ulcers, and esophageal cancer following HRT initiation. Results: Postmenopausal women on HRT had a significantly higher risk of GERD than premature menopausal women (17.13% vs. 9.44%; Risk Ratio 1.81, 95% CI 1.38–2.39, p < 0.0001). Interestingly, esophageal cancer was more prevalent in the premature menopause group (<0.93% vs. 0%, p = 0.0015). No significant differences were observed in Barrett’s esophagus or esophageal ulcer incidence between groups. Conclusions: In this large-scale EHR-based analysis, HRT was associated with a higher incidence of GERD in postmenopausal women, while women with premature menopause experienced a modestly increased rate of esophageal cancer. These findings suggest the need for personalized risk stratification when prescribing HRT. Further research should examine how HRT administration routes influence GI risk profiles and explore these trends in larger, more diverse populations.