Background Randomized controlled trials (RCTs) have demonstrated that low‐dose direct oral anticoagulants (DOACs), including rivaroxaban and apixaban, may help reduce the incidence of cancer‐associated venous thromboembolism (VTE). Methods A cost‐utility analysis was performed from the health sector perspective using a Markov state‐transition model in patients with cancer who are at intermediate‐to‐high risk for VTE. Transition probability, relative risk, cost, and utility inputs were obtained from a meta‐analysis of the RCTs and relevant epidemiology studies. Differences in cost, quality‐adjusted life‐years (QALYs), and the incremental cost‐effectiveness ratio (ICER) per patient were calculated over a lifetime horizon. One‐way, probabilistic, and scenario sensitivity analyses were conducted. Results In patients with cancer at intermediate‐to‐high risk for VTE, treatment with low‐dose DOAC thromboprophylaxis for 6 months, compared with placebo, was associated with 32 per 1000 fewer VTE and 11 per 1000 more major bleeding episodes over a lifetime. The incremental cost and QALY increases were $1445 and 0.12, respectively, with an ICER of $11,947 per QALY gained. Key drivers of ICER variations included the relative risks of VTE and bleeding as well as drug cost. This strategy was 94% cost effective at the threshold of $50,000 per QALY. The selection of patients with Khorana scores ≥3 yielded the greatest value, with an ICER of $5794 per QALY gained. Conclusions Low‐dose DOAC thromboprophylaxis for 6 months appears to be cost‐effective in patients with cancer who are at intermediate‐to‐high risk for VTE. The implementation of this strategy in patients with Khorana scores ≥3 may lead to the highest cost‐benefit ratio. A low‐dose direct oral anticoagulant appears to be cost‐effective versus placebo for preventing cancer‐associated thrombosis. Patients with the highest risk for thrombosis according to the Khorana score derive the most incremental benefit from a preventive strategy.