Together, these data showed that DKK3 was up-regulated when the miR-214-3p was inhibited by the cantharidin in the osteosarcoma cells; the up-regulated DKK3 prevented the GSK-3β from being phosphorylated, which further inhibited the β-catenin activation, nuclear translocation, and the downstream LEF1 translation, leading to an inhibited Wnt/β-catenin signaling activity in osteosarcoma cells, therefore, confirmed direct contribution of miR-214-3p/DKK3/GSK-3β/β-catenin/LEF1 axis in cantharidin suppressed osteosarcoma progression. This evidence concerns the gene LEF1 and osteosarcoma.