Proton Pump Inhibitors are used widely to manage many gastric acid-related conditions such as gastroesophageal disease, gastritis, esophagitis, Barrett's esophagus, Zollinger-Ellison syndrome, peptic ulcer disease, nonsteroidal anti-inflammatory drug-associated ulcers, and eradication, around the globe. This review article focuses on adverse effects associated with the long-term use of proton pump inhibitors. Various observational studies, clinical trials, and meta-analyses have established the adverse effects associated with the long-term use of proton pump inhibitors including renal disorders (acute interstitial nephritis, acute kidney injury, chronic kidney disease, and end-stage renal disease), cardiovascular risks (major adverse cardiovascular events, myocardial infarction, stent thrombosis, and stroke), fractures, infections ( infection, community-acquired pneumonia, and Coronavirus disease 2019), micronutrient deficiencies (hypomagnesemia, anemia, vitamin B12 deficiency, hypocalcemia, hypokalemia), hypergastrinemia, cancers (gastric cancer, pancreatic cancer, colorectal cancer, hepatic cancer), hepatic encephalopathy, and dementia. Clinicians including prescribers and pharmacists should be aware of the adverse effects of taking proton pump inhibitors for an extended period of time. In addition, the patients taking proton pump inhibitors for long-term should be monitored for the listed adverse effects. The American Gastroenterological association recommends a few non-pharmacological measures and the use of histamine 2 blockers to lessen gastrointestinal symptoms of gastroesophageal reflex disease and the utilization of proton pump inhibitors treatment if there is a definitive indication. Additionally, the American Gastroenterological association's Best Practice Advice statements emphasize deprescribing when there is no clear indication for proton pump inhibitors therapy.