Our previous study investigated the effects of differentiation inducted by flavonoids derived from a Chinese herb. In this study, we found that LW-218, a new synthesized flavonoid, inhibited proliferation and induced differentiation of acute myeloid leukemia cells. The IC50s of LW-218 in HL-60, U937, K562, and NB4 cell lines were all less than 5 μM, suggesting greater capacity than compounds we have reported. LW-218 induced differentiation effects including morphologic changes, NBT reduction, and both of CD11b and CD14 expression. Results of western blots and siRNA transfection revealed that LW-218 increased the LAP/LIP ratio of C/EBPβ which regulated monocytic differentiation of leukemia cells. Meanwhile, these differentiation effects could be attenuated by silencing PLSCR1 via siRNA transfection. In addition, regulation on LAP/LIP ratio, of C/EBPβ was properly mediated by PLSCR1 which was up-regulated by LW-218. All these results suggested that C/EBPβ was involved in regulation of PKCδ/PLSCR1 pathway during flavonoids-induced differentiation. LW-218 was a prospective differentiation inductor of AML cells and was requisite to proceed further investigation.