Molecular targeted cancer therapy is a rapidly developing field, driving progress toward greater treatment efficacy. However, targeted monotherapy often fails due to the development of multidrug resistance in tumors. The combination of multiple targeted agents emerges as a possible solution to enhance treatment outcomes by activating different signaling pathways. This study systematically investigates the combined effect of targeted agents for the oncomarkers HER2 and EpCAM on cancer cells. Specifically, the study examined the impact of anti-HER2 (DARP_9.29-LoPE) and anti-EpCAM (DARP_EC1-LoPE) immunotoxins on a panel of cancer cells expressing various levels of HER2 and EpCAM. Using the Chou-Talalay combination indices, the study revealed that cells with low HER2 expression and high EpCAM expression are not optimal targets for combined HER2/EpCAM therapy. In contrast, the most effective approach involves the usage of an equimolar ratio of immunotoxins for cells exhibiting high HER2 and moderate EpCAM expression, resulting in a synergistic therapeutic effect. These findings provide significant insights into optimizing combination anti-HER2/EpCAM therapies and hold promise for the development of more effective cancer treatment strategies.