Introduction: Warfarin is a highly effective oral anticoagulant; however, its use is confined due to a valid concern about bleeding. This systematic review investigates the drug-drug interactions that may occur in patients on warfarin therapy and the use of antimicrobials. Methodology: PubMed, Web of Science, Science Direct, EBSCO, and Cochrane library were searched. Study articles were screened by title and abstract using Rayyan QCRI then a full-text assessment was conducted. Results: Eleven studies were included, with a total of 83438 patients. The included studies have reported different antibiotics were associated with bleeding events in patients on warfarin therapy. Three studies associated reported GIT bleeding. Older adults and patients who underwent valve replacement surgery and were on warfarin therapy were found to have an increase in INR with associated antibiotic use. Conclusion: Patients on warfarin run the risk of a variety of drug interactions. Most interactions but not all—increase the risk of bleeding, and the majority of these are linked to higher international normalised ratios. The good news for doctors is that most common drug interactions with warfarin are triggered by a small number of well-known drug classes, and their effects are shown through a small number of pathways, many of which are clear. The risk of harm brought on by drug interactions can be decreased by being aware of these guidelines, using thoughtful prescription practises, and exercising judicious monitoring when new medications are added to regimens containing warfarin.