Proton pump inhibitors are among the most widely prescribed and frequently used medications worldwide, primarily indicated for the management of acid-related gastrointestinal disorders such as gastroesophageal reflux disease, peptic ulcer disease, Zollinger–Ellison syndrome, and for Helicobacter pylori eradication regimens. Their widespread and frequently protracted usage, including over-the-counter intake, has been facilitated by their potent acid-suppressive action and short-term safety profile. However, during the past 20 years, concerns regarding potential adverse effects of long-term proton pump inhibitor therapy have emerged. These problems span multiple organ systems and include nutrient deficiencies, bone fractures, renal disease, infections, cardiovascular and neurological effects, and possible associations with malignancy. The mechanism of proton pump inhibitors is carefully examined in this study, along with the evidence supporting their long-term adverse effects, and possible ways to reduce risks without reducing therapeutic benefit.