Background: Medicinal plants used in traditional Mexican medicine represent a valu-able source of bioactive compounds with potential anticancer activity. Beyond cyto-toxic potency, selectivity toward cancer cells over normal cells is a critical toxicologi-cal parameter for identifying safer therapeutic candidates. This study aimed to evalu-ate the selective cytotoxic and antiproliferative effects of extracts from four Mexican medicinal plants across human cancerous and non-cancerous cell lines. Methods: Hexane, acetone, and methanolic extracts from Semialarium mexicanum, Eryngium heterophyllum, Piper auritum, and Cochlospermum vitifolium were evaluated in a panel of human cancer cell lines and non-tumoral models, including primary human uterine fibroblasts (HUF). Cytotoxicity was assessed after 48 h of treatment using in-creasing extract concentrations, and selectivity indices were calculated. Cell cycle dis-tribution and nuclear morphology analyses were performed to explore antiprolifera-tive effects. Additionally, GC–MS-based chemical profiling was conducted on selected extracts to obtain a tentative characterization of major bioactive constituents. Results: The extracts exhibited differential cytotoxic profiles depending on plant spe-cies and solvent polarity. Semialarium mexicanum, particularly its hexane extract, showed the highest cytotoxic potency and selectivity toward HeLa cervical cancer cells, achieving selectivity indices higher than those observed for paclitaxel when compared with HUF cells. Hexane extracts of Semialarium mexicanum and Eryngium heterophyllum, were generally more active than polar extracts, whereas Piper auritum displayed limited cytotoxicity and Cochlospermum vitifolium showed moderate, sol-vent-dependent effects. Cell cycle perturbations and nuclear alterations supported an antiproliferative response. Chemical profiling suggested the presence of lipophilic triterpenoid-related compounds in non-polar extracts and phenolic constituents in polar fractions. Conclusions: These findings provide in vitro evidence of selective anticancer activity of Mexican medicinal plant extracts and establish a basis for future mechanistic stud-ies medicinal plant extracts and lay the groundwork for future mechanistic investigations.