CD96 has recently been shown as a negative regulator of mouse natural killer (NK)–cell activity, with Cd96-/- mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different tumor models. The antimetastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1), and IFN?, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti–CTLA-4, anti–PD-1, or doxorubicin chemotherapy. Blocking CD96 in Tigit-/- mice significantly reduced experimental and spontaneous metastases compared with its activity in wild-type mice. Co-blockade of CD96 and PD-1 potently inhibited lung metastases, with the combination increasing local NK-cell IFN? production and infiltration. Overall, these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases. Significance: This article illustrates the antimetastatic activity and mechanism of action of an anti-CD96 antibody that inhibits the CD96–CD155 interaction and stimulates NK-cell function. Targeting host CD96 is shown to complement surgery and conventional immune checkpoint blockade.