BACKGROUND: This study explored the prescribing patterns of proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs) across the UK during the COVID-19 pandemic, highlighting the dynamic relationship between emerging evidence, regulatory actions, and clinical practices. METHODS: Using a repeated cross-sectional design, prescription data from July 2019 to May 2024 were analyzed across England, Scotland, Wales, and Northern Ireland. Segmented regression analysis was employed to assess trends before and after January 2022, reflecting the impact of emerging evidence on prescribing behaviors. RESULTS: The results revealed a significant increase in famotidine prescriptions, from 57.56 to 303.31 per 100,000 population in England post-January 2022, reflecting early adoption of preliminary findings despite the lack of randomized controlled trial confirmation. Ranitidine prescriptions fell to near zero due to contamination concerns, while PPIs like omeprazole remained the most prescribed, with Wales reporting the highest post-2022 usage at 7445.71 per 100,000 population. CONCLUSIONS: Adherence to deprescribing guidelines was inconsistent, with a possibility that many PPI users lacked documented indications. Regional variations in prescribing trends highlighted differences in guideline implementation. These findings underscore the need for improved evidence dissemination and adherence to prescribing guidelines. Future research should include patient-level data and long-term evaluations to optimize healthcare practices.