The escalating use of complementary and alternative medicine (CAM) raises concerns, particularly among geriatric patients taking multiple medications. Notably, the doubled chance of major drug interactions between prescription and over-the-counter (OTC) drugs in older adults underscores the need for further research. This study aimed to evaluate clinically significant CAM and prescription medication interactions in a geriatric clinic, emphasizing the growing importance of understanding CAM implications in health care. A 2-year cross-sectional study, approved by the Institutional Review Board, enrolled 420 participants aged 65 and older from a geriatric primary care clinic. Participants completed a survey, and pharmacy students conducted chart reviews to evaluate potential CAM products and prescription medication interactions. Among the 420 participants-who were predominantly White females and who were taking supplements, OTC medications, or both-15.6% experienced potential drug interactions. Ginkgo biloba, garlic, and calcium were common contributors to major, moderate, and minor interactions, respectively, among supplements. Meanwhile, ibuprofen was among the contributors to major and moderate interactions among OTC medications. Most supplements and OTC medications were disclosed to health care professionals. However, there was a lack of investigation by health care professionals regarding CAM use, emphasizing a discrepancy between patient-reported and physician-inquired CAM usage. This study highlighted the significant use of CAM and/or OTC medications, particularly among vulnerable older adults, revealing a concerning 15.6% rate of potential drug interactions. The findings emphasized the need for awareness among health care practitioners and standardized CAM surveys to enhance accuracy and patient safety.