Cytarabine (Ara-C) has become cornerstones for the treatment of hatmatological malignancies for several decades; however, it still faces serious challenges in clinical applications due to its side effects such as hand foot syndrome (HFS) and stomatitis. Therefore, considerable researchers have devoted to looking for the new derivative with desirable activity and low toxicity. A new prodrug based on the conjugation of cytarabine with lauric acid (LA-Ara) was synthesized in our group, and it could self-assemble into nanofibers (NFs) in aqueous solution with high drug loading (57 wt%). The lauric acid moiety protects NH2 group of from the enzymatic attachment and simultaneously raises the lipophilicity of Ara-C, thus obviously prolongs its plasma half-life. The oil/water partition coefficient (lg P) and the permeability of cell membrane of LA-Ara were obviously increased compared with Ara-C. Furthermore, the in vitro gastrointestinal stability results indicated the prodrug was suitable to be administrated orally. In the current study, the in vitro cytotoxicity and in vivo anti breast cancer experimental results indicate LA-Ara markedly improved antitumor activity compared with free Ara-C. The favorable safety evaluations elucidated its potentiality for oral alternative treatment to Ara-C. Importantly, LA-Ara can effectively decrease the incidence of toxic effects (HFS and stomatitis) of Ara-C, thereby exhibiting favorable skin safety profile. Overall, these results indicated the LA-Ara would be an excellent candidate for further clinical investigation and simultaneously highlight the prospects of Ara-C prodrug strategies in solid tumors therapy.