Venous thromboembolism (VTE) is associated with high recurrence, mortality, and cost burden. Direct oral anticoagulants (DOACs) are currently used for VTE treatment, and they offer more benefits over warfarin, despite being more expensive. There is no consensus on the most cost-effective DOAC agent, especially in VTE. This systematic review aims to summarize the comparative cost-effectiveness studies and their impact among DOACs in the treatment of VTE. Literature systematic review of PubMed, Embase, and EconLit was conducted in February 2018 to identify all cost-effectiveness studies of DOAC for the treatment and prevention of VTE. Two independent investigators systematically collected search results and assessed the quality of the studies. The search identified 7 articles, all of which had dabigatran and rivaroxaban as comparators, 6 of which also included apixaban, and 2 of which also had edoxaban. Results of 3 articles concluded that apixaban is a dominant strategy compared to other DOACs in terms of Incremental Cost-Effectiveness Ratio (ICER) in the treatment and prevention of recurrent VTE. One article compared rivaroxaban and dabigatran, with the latter dominating rivaroxaban in terms of ICER. Compared to other DOACs, 2 articles reported apixaban being associated with highest annual total medical cost avoidance of US$4244 and US$4440 per patient-year (ppy), respectively. One article reported that apixaban had the highest annual total medical cost differences of US$918 ppy compared to other DOACs. This systematic review demonstrates that apixaban is considered a cost-effective strategy for VTE treatment and prevention of recurrent VTE.