Background: Colon cancer is one of the leading causes of cancer-related deaths today. Crucial research continues for the ideal chemotherapy. In this context, natural compounds of plant origin play an important role in the development of new anticancer drugs. Methods: In this study, the effects of Consolida orientalis ethanol extract (flower parts), Smyrnium rotundifolium ethanol extract (aerial parts), and Euphorbia virgata ethanol extract (aerial parts) samples on HT-29 (human colorectal adenocarcinoma cell line) and healthy CCD-18Co (human normal colon fibroblast cell line) were investigated for the first time in the literature by applying 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test within the scope of in vitro cytotoxicity analysis. Results: As a result of the study, it was observed that all plant extracts were most effective at 72 h. S. rotundifolium ethanol extract (aerial parts) was found to be the most effective on the HT-29 cell line. Both the higher cell viability of C. orientalis in healthy cells applied to it compared to S. rotundifolium and its effectiveness on colon cancer cell lines make C. orientalis more advantageous. Conclusions: When evaluating the efficacy of extracts on cancer cells, the load on healthy cells should be taken into account. Therefore, C. orientalis ethanol extract (flower parts) was found to have the potential to be a chemotherapeutic agent against colon cancer. Chemical reactivities of the dominant components of bioactive components were analyzed via Conceptual Density Functional Theory-based calculations. The power of the interactions with EGFR kinase of these compounds is checked via Molecular Docking Calculations. It was noted that Chlorogenic acid, which is the most reactive bioactive component, has a stronger binding to the mentioned enzyme.