Helicobacter pylori remains a crucial factor in the development of gastrointestinal (GI) diseases including chronic gastritis, peptic ulcer disease (PUD) and gastric cancer, even decades after its discovery. This review summarizes the advances in the field of H. pylori and non-malignant diseases of the upper GI tract and includes the most relevant studies on this topic published between April 2020 and March 2021. Here we include the published data on associations between H. pylori infection and diseases, such as gastroesophageal reflux disease (GERD), Barrett’s esophagus, eosinophilic esophagitis (EoE), PUD, gastritis, gastric polyps and celiac disease. Observations over the past 25 years highlight the trends in decreasing prevalence of gastric and duodenal ulcer while the rate of reflux esophagitis increased. A meta-analysis links the prevalence of GERD with H. pylori eradication. Other studies support the inverse correlation of H. pylori infection with Barrett’s esophagus. Large cohort studies highlight the negative association between H. pylori infection and the prevalence of fundic gland polyps. On the contrary, successful eradication of H. pylori resulted in a significant increase in the clearance rate of hyperplastic polyps. Novel data on H. pylori infection, microbiome, and immune-triggered diseases highlight the potential role of the microbiome in disease development, its impact on mucosal injury in patients with H. pylori infection and even its potential value in H. pylori management. An inverse association of H. pylori infection and several immune diseases, including asthma and EoE remains a scientific focus.