Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT- and MBNL2-mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.