Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies, and 40% of cases are related to mutation of the oncogene KRAS. However, no KRAS-targeting drugs are currently available for cancer treatment, and patients with KRAS mutations are insensitive to anti-EGFR therapy, which is often used for CRC. To improve treatment options, a new study tested the combined effects of the drugs artesunate and WNT974 on KRAS-mutant CRC. In vitro, the combination synergistically reduced CRC growth and decreased KRAS protein levels and activity, while inducing KRAS degradation via the ubiquitin–proteasome pathway, thereby reducing the oncogene’s influence. Specifically, the induced KRAS degradation was mediated by upregulation of ANAPC2, as well as upregulation of β-TrCP and GSK-3β. In addition, the combination treatment suppressed the PI3K/Akt/mTOR pathway, which is downstream of KRAS and supports tumor growth. In vivo, CRC tumors in mice treated with both drugs grew slower and remained smaller than control mice or mice treated with either drug alone. Although the pharmacodynamics, pharmacokinetics, and toxicity of the combination therapy remain to be determined, the results identify combined artesunate and WNT974 administration as a promising strategy for KRAS-mutant CRC, providing hope for the future treatment of this intractable disease.