<b><i>Introduction:</i></b> The aim of this study was to study the relationship between the formation of gastric fundic gland polyp and gastric hyperplastic polyp (HP) and the changes of gastric juice microenvironment. <b><i>Methods:</i></b> The proton-pump inhibitor (PPI) applications to patients were recorded. Gastric juices and biopsy polyps were collected for pathological examination, <i>H. pylori</i> tests, biomarkers, and <i>MUC1</i>, <i>MUC2</i>, <i>MUC5AC expression</i> measurement. <b><i>Results:</i></b> Among 34,892 patients, the detection rate of gastric fundic gland polyps was significantly higher than that of gastric HPs (<i>p</i> < 0.01). The incidence rate of gastric fundic gland polyp and gastric HP in PPI users (<i>n</i> = 3,886) was higher than that of non-PPI users (<i>p</i> < 0.01). The occurrence of polyp was positively related to the duration of PPI application and the <i>H. pylori</i>-positive rate. The bile reflux rate between fundic gland polys group (17.61%) and HPs (28.67%) was significantly different (<i>p</i> < 0.01). The levels of gastric juice Gastrin-17, epidermal growth factor (EGF) and MUC<sub>2</sub> from patients with gastric fundic gland polyps and gastric HPs were higher than those in the control group (<i>p</i> < 0.01). However, patients with gastric fundic gland polyps and HPs had significantly lower gastric juice PGE<sub>2</sub> and MUC5AC (<i>p</i> < 0.01). <b><i>Conclusion:</i></b> PPI application, <i>H. pylori</i> infection, and bile reflux are the potential risk factors for formation of fundic gland polyps and HPs. The potential mechanism of polyps’ formation can be related to the levels of Gastrin-17, EGF, MUC<sub>2</sub>, PGE<sub>2</sub>, and MUC5AC in gastric juice.