Background <p>Colorectal cancer (CRC) has a high global incidence and mortality rate. Modern CRC treatment is largely limited due to its high recurrence rate, as well as treatment toxicity and drug resistance. Against this background, phytochemicals are attracting attention as promising candidates for cancer treatment due to their low toxicity levels and various pharmacological activities. <i>Calystegia soldanella</i>, a halophyte native to the Korean coastline, has been reported to exert antioxidant and anticancer effects, but the underlying molecular mechanisms remain unclear.</p> Objectives <p>In this study, we investigated the antioxidant and anticancer effects of <i>C. soldanella</i> extracts on the viability of the CRC cell line HCT116.</p> Results <p><i>Calystegia soldanella</i> extracts collected from Myeonjeon-ri significantly reduced HCT116 cell viability (IC₅₀: 9.614&#xa0;µg/mL). In contrast, <i>C. soldanella</i> extracts collected from Hanmun-ri did not reach the IC₅₀ value within the tested concentration range. Both <i>C. soldanella</i> extracts disrupted Ca²⁺ homeostasis by increasing cytosol and mitochondrial Ca²⁺ accumulation, promoting reactive oxygen species (ROS) production, and significantly upregulating inflammation-related genes, including <i>IL13</i>, <i>IL18</i>, <i>IL18R1</i>, <i>IL21</i>, and <i>CXCL1</i>. These results suggest that <i>C. soldanella</i> induces apoptosis in HCT116 cells by dysregulating Ca²⁺ homeostasis and increasing ROS-mediated stress, while simultaneously activating apoptosis and inflammatory signaling pathways. Moreover, regional differences in <i>C. soldanella</i> activity against HCT116 cells demonstrate the importance of the growth environment in forming metabolites or bioactive compounds in plants.</p> Conclusion <p>Collectively, our study findings reveal the molecular biological mechanisms of <i>C. soldanella</i>, suggesting its potential as a candidate or therapeutic adjuvant for CRC treatment.</p>