Colorectal cancer (CRC) ranks among the leading causes of cancer-related dea ths worldwide, and the rising incidence and mortality of CRC underscores the urgent need for better understanding and management strategies. Icaritin (ICA) is the metabolites of icariin, a natural flavonoid glycoside compound derived from the stems and leaves of Epimedium. It has broad spectrum antitumor activity and inhibits the proliferation, migration, and invasion of CRC cells, and causes S phase cell cycle arrest. It exerts its antitumor effects against CRC through repressing autophagy to promote CRC cell apoptosis via interfering the HSP90-TXNDC9 interactions. The safety and efficacy of ICA are also affirmed in a mouse xenograft model. Additionally, to test whether ICA exerts synergistic effects with low-temperature photothermal therapy (LTPTT), a novel nanodrug delivery system, employing SiO2 nanocarriers, is designed aiming to load ICA with photothermal materials polydopamine (PDA), and folic acid (FA). This SiO2/Ica-PDA-FA multifunctional nanocomposite actively targets tumor tissues through the high affinity of FA for cancer cells. Once internalized, the acidic intracellular environment triggers the controlled release of ICA, inhibiting HSP90-TXNDC9 interactions. By LTPTT and ICA drug therapy under near-infrared illumination, a dual synergistic antitumor effect is achieved, holding promise for enhancing therapeutic outcomes in CRC treatment.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.