<p>Colorectal cancer remains a leading cause of cancer-related death, and there is an urgent need for new therapies that can specifically induce tumor cell apoptosis. Plant polyphenols have emerged as promising alternatives for cancer treatment. <i>Flourensia cernua</i> and <i>F. retinophylla</i> are polyphenol-rich plants native to northern Mexico, known for their use in traditional medicine, and recently reported to have anti-inflammatory and antimicrobial properties; however, their anticancer effects remain poorly studied. This study aimed to evaluate the ability of polyphenolic extracts from <i>F. cernua</i> and <i>F. retinophylla</i> to induce apoptosis in HT-29 human colon adenocarcinoma cells in vitro and to explore the mechanisms of cell death triggered by these extracts. Polyphenolic extracts were prepared from dried leaves using ethanol and analyzed for antioxidant activity and polyphenolic composition. HT-29 cells were treated with different concentrations, and cytotoxicity was measured by MTT assay. Apoptosis was analyzed through intrinsic and extrinsic pathways, caspase activity, and detection of apoptosis-related proteins via Western blot and antibody array. Both <i>Flourensia</i> extracts are rich in polyphenols and exhibit high antioxidant capacity. Treatment with the extracts caused dose-dependent growth inhibition of HT-29 cells. <i>F. cernua</i> extract triggered cytochrome c and SMAC release, indicating activation of the intrinsic pathway, and also upregulated death receptor proteins and caspase-8, indicating engagement of the extrinsic pathway. <i>F. retinophylla</i> produced a weaker response, mainly modulating intrinsic-pathway markers. Both extracts also increased caspase-3 levels, consistent with engagement of apoptotic signaling. These findings demonstrate the potential of <i>Flourensia</i>-derived extracts as alternative anticancer agents with apoptosis-inducing potential in human colon adenocarcinoma cells.</p>