<p>Vitamin B12 deficiency is a prevalent but often underdiagnosed issue that occurs most commonly in geriatric patients. The clinical manifestations are often subtle; however, the potential for severe complications, particularly hematological or neuropsychiatric, warrants investigations of all patients who present with vitamin deficiency. This literature review investigates the risk of vitamin B12 deficiency associated with proton pump inhibitors (PPI), metformin, and H2 receptor antagonists through the lens of polypharmacy. These drugs are frequently prescribed to the elderly, and although they are useful in treating long-term illnesses like GERD, type 2 diabetes, and peptic ulcer disease, they often can interfere with the body's ability to absorb vitamin B12 through various physiological pathways. The purpose of this review is to determine the risk of vitamin B12 deficiency in older patients taking H2 blockers, PPIs, and metformin, as well as how polypharmacy affects this risk. In gathering information for this study, we searched PubMed, Scopus, and Google Scholar for articles published in the last 20&#xa0;years. Articles that were not in English or did not have a clear methodological approach were not included in this study. Long-term use of all three drug classes was found to be significantly associated with lower serum vitamin B12 levels; metformin and PPI users exhibited a dose and duration-dependent pattern. Combining these medications raises the risk even further, and age-related physiological changes and supplement noncompliance can exacerbate vitamin B12 deficiency. These findings highlight the need for proactive B12 level monitoring for elderly patients on long-term medication regimens. This monitoring should include screening and tailored supplementation for any potential deficiencies. Improving overall patient outcomes and reducing the burden of complications resulting from deficiencies would be the goals.</p>