Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and antithrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: −5.38%, 95% CI: −11.92, +1.16, p = 0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12 months (WMD: −7.64%, 95% CI: −16.58, +1.29, p = 0.094) or ≥12 months (WMD: −0.62%, 95% CI: −8.40, +7.17, p = 0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: −1.44, +2.93, p = 0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12 months (WMD: +2.26%, 95% CI: −3.14, +7.66, p = 0.411) or ≥ 12 months (WMD: +0.06%, 95% CI: −1.16, +1.28, p = 0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: −0.39, +1.19; p = 0.317) and ATIII (slope: −0.17; 95% CI: −0.54, +0.20; p = 0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone.