In this study, 21 new honokiol derivatives were synthesised, and their anti-cancer properties were investigated. Among these, compound
1g
exhibited the most potent cytotoxic activity against human nasopharyngeal carcinoma CNE-2Z cells, human gastric cancer SGC7901 cells, human breast cancer MCF-7 cells, and mouse leydig testicular cancer I-10 lines with IC
50
values of 6.04, 7.17, 6.83, and 5.30 μM, respectively. Compared to the parental compound,
1g
displayed up to 5.18-fold enhancement of the cytotoxic effect on CNE-2Z cells. We further demonstrated that
1g
inhibited cell growth, suppressed migration and invasion, and induced apoptosis of CNE-2Z cells by down-regulating HIF-1α, MMP-2, MMP-9, Bcl-2, Akt and up-regulating Bax protein levels. Transfection of CNE-2Z cells with HIF-1α siRNA reduced cell migration and invasion. In addition,
in vivo
experiments confirmed that
1g
inhibited tumour growth in CNE-2Z cell-xenografted nude mice with low toxicity. Thus, our data suggested that
1g
was a potent and safe lead compound for nasopharyngeal carcinoma therapy.