Anoikis-sensitization activity of imperatorin, an active furanocoumarin component of Angelica dahurica root, is reported herein for the first time in human lung cancer H23 cell. The present study demonstrated that the imperatorin treatment at sub-toxic concentrations enhanced human lung cancer H23 cell apoptosis after detachment. A western blot analysis of a major protein involved anoikis showed that imperatorin significantly increased p53 protein level which subsequently down-regulated Mcl-1 protein and up-regulated Bax while it had a minimal effect on Bcl-2 expression. In addition, imperatorin exhibited a strong inhibitory effect on the anchorage-independent growth of the cells supporting the anti-metastasis potential of imperatorin. Further, this study demonstrated that imperatorin sensitizes anoikis in another lung cancer cells, namely H292 and A549. Because anoikis was shown to be a critical hindrance preventing cancer cell metastasis, the knowledge regarding such an activity and an underlying mechanism may lead to the development of this compound for a cancer therapy.