Nitroimidazole antibiotics are the mainstay of treatment of invasive amebiasis; however, few comparative studies of applicable antibiotics are available. Evidence of sporadic clinical failure and rare reports of metronidazole resistance have led to the investigation of novel antiamebic therapeutics. The goal of this study was to examine drug efficacy in both in vitro and in vivo models of intestinal amebiasis. We studied six current and three novel drugs. Many drugs, including metronidazole, nitazoxanide, and nitazoxanide derivatives, were shown to be potently inhibitory in vitro. However, metronidazole remained the most effective in vivo, both in preventative and curative regimens, underscoring the value of animal models in evaluating future therapies.