The our previous study synthesized the chrysin-chromene-spirooxindole hybrids 3, and further found compound 3e had good antitumor activity against A549 cells in vitro through multi-target co-regulation of the p53 signalling pathway to inhibit the proliferation of A549 cells. This study was designed to evaluate the antitumor effects of compound 3e on Lewis lung carcinoma of C57BL/6 mice in vivo. Compound 3e significantly inhibited the growth of transplanted tumors in C57BL/6 mice and induced the apoptosis of tumor cells. Further studies showed that compound 3e activates and expands the anti-cancer activity of p53 by inhibiting the expression of MDM2, Akt and 5-Lox proteins, accordingly promotes the expressions Bax and inhibit the Bcl-2 protein, the release of Cyt c as well, which resulted in the activation of apoptotic pathway in tumor cells eventually. Moreover, Compound 3e inhibited tumor metastasis by down-regulating VEGF, ICAM-1 and MMP-2 protein expression and angiogenesis. These results suggested that compound 3e exerts an effective antitumor activity in vivo through activating the p53 signaling pathway, which could be exploited as a promising candidate for the development of new anti-tumour drugs.