Drug-drug interactions are becoming more frequent in health care as a risk factor responsible for many emergency cases and clinic visits. Polypharmacy is affecting more and more people, and it is higher among the elderlies who are on a high number of medicines. Self-medication practices are also common among elderly patients, which may be problematic if it was combined with polypharmacy. This cross-sectional study showed a high prevalence of polypharmacy, self-medication practices, and drug-drug interactions among elderly patients in the Syrian Arab Republic. Caution should be taken when prescribing chronic medicines, as well as awareness about the potential drug interactions while practicing self-medication should be raised.