<p>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, highlighting the critical need for the development of innovative and effective therapeutic strategies. Baicalein, a bioactive flavonoid derived from <i>Scutellaria baicalensis</i>, has emerged as a promising anticancer agent with multifaceted effects against colorectal cancer. This work summarizes into the molecular and immunomodulatory mechanisms underlying baicalein’s anticancer activity. Baicalein inhibits proliferation, suppresses metastasis, induces apoptosis, and modulates key pathways like PI3K/Akt, MAPK, and TLR4/NF-κB. It enhances the tumor microenvironment by promoting immune cell infiltration, regulating cytokines, and activating CD4 + and CD8 + T cells, amplifying antitumor immunity. By targeting critical oncogenic and immune pathways, baicalein disrupts tumor progression while simultaneously enhancing immune recognition and suppressing tumor-promoting mechanisms in CRC. Additionally, baicalein influences redox homeostasis by modulating reactive oxygen species (ROS) generation and restoring oxidative balance, thereby impacting cancer cell survival and proliferation. Its anti-oxidative properties further mitigate tumor-promoting oxidative stress while sensitizing CRC cells to apoptosis. Baicalein have poor solubility and rapid metabolism limits its effectiveness against colorectal cancer, where nanotechnology-based drug delivery can overcome these challenges. By using nanoparticles (NP) and other nano-carriers to improve stability, targeting, and controlled release, baicalein’s anticancer potency and safety can be significantly enhanced for future CRC therapies. Thus, baicalein-NP conjugates can strengthen the immune defense and blocks cancer-promoting signals in colorectal cancer.</p> Graphical abstract <p>Effect of baicalein on colon cancer signaling with immunomodulation and oxidative stress.</p> <p></p>