Aim To systematically evaluate the effect of non-vitamin K antagonist oral anticoagulants (NOAC) on liver function. Methods The PubMed, Embase, Cochrane Library, Wanfang, CNKI and VIP databases were searched to collect randomized controlled trials (RCT) related to non-vitamin K antagonist oral anticoagulant treatment published openly before June 0,3. Data were extracted according to the inclusion criteria. The quality of the included studies was evaluated. Meta-analysis was performed on the related data using R language. Results A total of 22 RCT studies were included, with 64 063 patients receiving non-vitamin K antagonist oral anticoagulant treatment. Compared with the control group, non-vitamin K antagonist oral anticoagulants did not increase the risk of abnormal liver function (alanine transaminase (ALT)＞3 ULN) (RR＝0.2,5%CI:0.61～0.84, I²＝59%, P＜0.01), or the risk of severe liver injury (ALT＞3 ULN combined with total bilirubin (TBIL)＞2 ULN) (RR＝0.8,5%CI:0.80～1.19, I²＝0%, P＝0.01). When used for preventing deep vein thrombosis after orthopedic surgery, compared with the control group, non-vitamin K antagonist oral anticoagulants reduced the risk of abnormal liver function (RR＝0.9,5%CI:0.61～0.79, I²＝0%, P＜0.01). Conclusions Non-vitamin K antagonist oral anticoagulants have high liver safety. The occurrence of non-vitamin K antagonist oral anticoagulant-associated liver injury may be dose-dependent. Regular monitoring of liver function is recommended when applying non-vitamin K antagonist oral anticoagulants clinically to patients with a history of liver disease.