Venous thromboembolism is a common complication among cancer patients with an estimated risk of 20%. American Society of Clinical Oncology guidelines recommend direct oral anticoagulants for long-term anticoagulation but caution the use of direct oral anticoagulants because of drug-drug interactions with antineoplastic therapies. The clinical impact of these drug-drug interactions is yet to be studied in clinical trials. This study aims to evaluate the effect of the drug-drug interactions on venous thromboembolism recurrence and bleeding. This is a retrospective cohort study that included cancer patients with venous thromboembolism receiving apixaban or rivaroxaban with antineoplastic therapy. The impact of the drug-drug interaction was determined by its effect on the rates of venous thromboembolism recurrence and bleeding in patients with a drug-drug interaction compared to patients with no drug-drug interaction. The primary composite endpoint of venous thromboembolism recurrence and bleeding events occurred in 65% versus 62% of patients in drug-drug interaction and non-drug-drug interaction groups accordingly. There was a higher rate of venous thromboembolism recurrence and minor bleeding events with anti-mitotic microtubule inhibitors and a higher rate of minor bleeding events with hormonal therapy and alkylating agents. Among the drug-drug interaction group, there were no major bleeding events reported with mild drug-drug interactions when compared to moderate-to-severe drug-drug interactions. There was no difference in time to venous thromboembolism recurrence between rivaroxaban and apixaban. Due to small sample size, our study results could not confirm a higher risk of bleeding or venous thromboembolism recurrence with the drug-drug interactions. Further prospective study is warranted, but clinicians should be aware of these drug-drug interactions and identify them using available literature.