Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rigosertib were designed. Among them, compound 29 showed the most potent antitumor activity in vitro with IC50 values at the nanomolar level against the tested tumor cell lines and 1000-fold higher than cisplatin against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP cells), while it showed only moderate cytotoxicity against normal cells (HEUVC cells). Compound 29 could clearly disturb signaling transduction between RAS and CRAF by directly bonding to CRAF and inhibit CRAF activation. Besides, the enhanced intracellular platinum level made 29 more potent than cisplatin in DNA damage, reactive oxygen species accumulation, and mitochondrial membrane potential decrease. Moreover, 29 induced apoptosis by the endogenous pathway and efficiently inhibited tumor growth in the A549 xenograft model without side effects.