The long-term use of proton pump inhibitors (PPIs) can lead to increased gastric pH, hypochlorhydria and in some cases to achlorhydria when compared to other acid-suppressing agents like histamine-2 (H2) receptor blockers and antacids. These consequences by the use of long-term PPIs may lead to significant vitamin (B₁₂ and C) and mineral (iron, calcium and magnesium) deficiencies which needs gastric acid for their absorption and bioavailability. Long-term use of PPIs by the pregnant patients may impose a potential risk of congenital malformations. Various studies have recommended the life style modifications and antacid use as first choice among pregnant womens by preserving PPIs (omeprazole as a safe choice of PPI) for severe conditions of gastroesophageal reflux disease. The long-term acid suppression by PPIs can also lead to enteric, respiratory and urinary tract infections. The hypochlorhydria by chronic PPIs use may induce hypergastrinemia, which ultimately mediates the gastric polyps, gastric carcinoids and gastric cancer. The concomitant use of PPIs with antiplatelet drugs like clopidogrel can impose the patients to major adverse cardiac events. This review has enlisted the comprehensive information regarding the adverse effects induced by long-term use of PPIs and their possible relations. Considerable studies like case-control, randomized trials, cohort studies and meta-analysis were reported in supporting these adverse effects. The clinicians and patients should be cautious about these effects so that they can avoid the serious outcomes. PPIs should be avoided for long-term use mainly in older adults unless there is a proper indication.