Colorectal cancer (CRC) is the third most common worldwide. Depending on its stage, chemotherapy is usually given after surgery when CRC has already metastasized to other organs like the liver or lungs. Unfortunately, the current antineoplastics used for CRC therapies involve toxicity and side effects due to their lack of site-specificity. To overcome the drawbacks of heavy chemotherapy, this study proposes to assess the efficacy of thymoquinone (TQ), a bioactive constituent of black seeds (), as an antiproliferative and pro-apoptotic agent on an experimental CRC model in mice. TQ was encapsulated in lipid nanocapsules (LNCs), used as nanocarriers, in order to increase its specificity and cell absorption. TQ-loaded LNCs (TQ-LNCs) have a diameter of 58.3 ± 3.7 nm and 87.7 ± 4.5% TQ encapsulation efficiency. In turn, studies showed that the intratumoral administration of TQ-LNCs decreased the tumor size in colorectal cancer bearing mice compared to the control group. TQ-LNCs were more effective than free TQ for inducing tumor cell death. These results highlight the potential of TQ entrapped in LNCs as an anticancer agent for CRC treatment.