Colorectal cancer (CRC) treatment with standard chemotherapeutics such as capecitabine (CAP) and irinotecan (IRT) is frequently limited by toxicity and resistance. To identify novel adjuvant strategies, we investigated the dichloromethane–methanol (DM) Soxhlet extract of the red alga Jania rubens, previously shown to exert intrinsic antiproliferative effects via reactive oxygen species (ROS) induction, inhibition of epithelial–mesenchymal transition (EMT), and suppression of TET enzymes. The present study evaluated the effect of the DM extract in combination with chemotherapeutic agents in HCT-116, Caco-2, and HT-29 colorectal cancer cell lines, assessing its potential to enhance treatment response. Co-treatment with the DM extract significantly enhanced the cytotoxic and anti-migratory effects of CAP and IRT in HCT-116 and Caco-2 cells. Combination treatment also impaired long-term clonogenic survival, suggesting the inhibition of therapy-resistant subpopulations. Flow cytometric analysis (Annexin V-FITC/PI) revealed a dose-dependent increase in apoptosis in HCT-116 cells following DM treatment. Western blot analysis further supported the pro-apoptotic activity of the DM extract by demonstrating reduced BCL-2 protein expression. The extract additionally modulated the mRNA expression levels of cytokines (TNF-α, IL-6, and IL-10), suggesting potential immunomodulatory effects in colorectal cancer cells. Notably, co-administration of IRT and the DM extract enhanced apoptosis, primarily through the downregulation of the anti-apoptotic gene BCL-2. Together, these findings indicate that the Jania rubens DM extract modulates multiple cellular pathways and enhances the response to conventional CRC chemotherapeutic agents.