Colorectal cancer (CRC) is the second most common cause of cancer incidence worldwide. Oral drug delivery systems (ODDS) have shown great promise for CRC therapy, but the delivery efficiency is still challenged by the dense intestinal mucus barrier and nonspecific interception of abnormally proliferated pathogenic bacteria. Herein, self‐thermophoretic nanoparticles (CTPB) is presented to enhance intestinal mucus penetration and reduce pathogenic bacteria interception in CRC for efficient drug delivery. The nanoplatform introduces hollow mesoporous copper sulfide and is asymmetrically sprayed with titanium dioxide as the self‐thermophoretic matrix. Based on the close relationship between pathogenic bacteria and CRC, the nanoplatform is camouflaged by the biomimetic membrane of Staphylococcus aureus to precisely anchor in the intestinal segment of CRC. After near‐infrared laser irradiation, CTPB can effectively increase the intestinal mucus penetration efficiency by 2.7 folds, and decrease the pathogenic bacterial interception by 3.5 folds via the self‐thermophoretic propulsion force. In orthotopic CRC‐bearing mice, CTPB vastly improved the drug delivery efficiency to CRC after oral administration, thus showing a 99.4% antitumor rate after three weeks of treatment, which provides new insight into oral drug delivery for CRC therapy. The delivery efficiency of oral nanoparticles is always limited by intestinal mucus and pathogenic bacteria interception. A self‐thermophoretic nanoparticle is developed for colorectal cancer therapy through penetrating intestinal mucus and detaching from pathogenic bacteria. With improved delivery efficiency, the nanoparticles showed a 99.4% antitumor efficiency in vivo, and provides a new strategy for orally targeted therapy of colorectal cancer.