A series of 25 novel quinolino-stilbene derivatives were designed, synthesized and evaluated for their potential as anticancer agents. Three of them not only displayed quite potent antiproliferative activity with IC50 values<4μM but also showed approximately twofold selectivity against cancer cells, compared to non-cancerous cells. Three other compounds exhibited comparatively good activity with IC50 values in the range of 4-10μM, and the rest was moderately active or inactive. One of these viz. 3-[E-(4-fluorostyryl)]-2-chloroquinoline (compound 7B) caused substantial DNA damage and arrested cell cycle in S phase. Interestingly, 7B was very active against MDA-MB468 (IC50=0.12μM), but not against other cell lines examined. Compound 3-[Z-(3-(trifluoromethyl)styryl)]-2-chloroquinoline (12A), the most effective against all cancer cell lines examined, caused prolonged cell cycle arrest at mitosis and eventually apoptosis. Data from an in vitro study showed that compound 12A inhibited microtubule polymerization in a similar fashion to nocodazole. Further study using in silico molecular modeling revealed that 12A causes the impediment of microtubule polymerization by binding to tubulin at the same cavity where podophyllotoxin binds.