Previously, we discovered a novel class of salicylhydrazide compounds with remarkable activity in hormone-dependent and -independent human cancer cells. We then designed and synthesized numerous analogues. Among these analogues, a quinoxalinhydrazide compound, SC144, exhibited desirable physicochemical and drug-like properties and therefore was selected for further preclinical investigation. In the present study, we evaluated the in vitro activity of SC144 in a range of drug-sensitive and -resistant cancer cell lines as well as its in vivo efficacy in MDA-MB-435 and HT29 mice xenograft models. The broad-spectrum cytotoxicity of SC144 is especially highlighted by its potency in ovarian cancer cells resistant to cisplatin, breast-cancer cells resistant to doxorubicin, and colon cancer cells resistant to oxaliplatin. Furthermore, its activity was independent of p53, HER-2, estrogen and androgen receptor expressions. We also examined the effect of SC144 on cell cycle progression and apoptosis in select cell lines. Considering its cytotoxicity profile in a variety of in vitro and in vivo cancer models as well as its effects on cell cycle regulation and apoptosis, SC144 appears to represent a promising agent for further clinical development.