Introduction 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. Methods 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. Results 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. Conclusion 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.