The anoikis-sensitization activity of imperatorin, an active furanocoumarin component of Angelica dahurica root, is reported herein for the first time. 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 showed that imperatorin significantly enhanced the 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, an anchorage-independent growth assay was performed to support the anti-metastasis potential of imperatorin. Consistent with anoikis assay, imperatorin exhibited a strong inhibitory effect on the anchorage-independent growth of the cells. Further, this study demonstrated that imperatorin sensitizes anoikis in other lung cancer cells, namely, H292 and A549. Because anoikis was shown to be a critical hindrance in 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.