In the present review we summarized current knowledge about significant interactions (DIs) of direct oral anticoagulants (DOACs) with other medications frequently prescribed to elderly patients with cardiometabolic diseases. Literature search was performed using PubMed from 1990 to October 2020. Randomized clinical trials (RCTs), subgroup analyses from RCTs, longitudinal studies, case series and case reports were included. Only studies in humans were considered. Elderly was defined as ≥75 years. Assessment of DIs with DOACs is often tricky because of the lack of validated tools to routinely assess magnitude of their anti-coagulation effect. Most of reports in the cardiometabolic area regarded the classes of anti-antiarrhythmic, lipid-lowering and platelet-inhibitors drugs, namely drugs that are widely used to reduce cardiovascular risk in patients with common metabolic diseases. Reports about elderly are limited in general, and it is not known whether certain types of DIs occur more frequently in elderly subjects. DIs were more frequently reported in association with dabigatran, which however has been available for a longer period of time compared with other DOACs. In most cases, no complete information about dosages of medications was available. DIs of DOACs leading to adverse events (both ischemic and bleeding ones) were generally facilitated by older age, polymedication and impaired renal function. Further studies should be carried out to properly investigate DIs of DOACs with cardiometabolic drugs in elderly patients, with particular focus on differences between DOACs and the influence of different dosages.