Colorectal cancer (CRC) is one of the most common types of cancers in humans and is closely linked to the global cancer-related mortalities worldwide. Molecular pathological epidemiology studies can reveal the risk factors of CRC and contribute to biomarker research and precision medicine. The current clinical treatment for CRC mainly involves surgery and chemotherapy. However, because of the occurrence of side effects and the emergence of drug resistance, there is an urgent need to find new and more effective drugs for CRC treatment. An increasing number of studies have demonstrated that many natural products possess effective anti-CRC effects and may serve as alternative chemotherapy agents for CRC treatment. In this review, we summarize the natural products with anti-CRC effects from different sources based on the chemical structures such as alkaloids, polysaccharides, polyphenols, terpenoid, unsaturated fatty acids, and discuss the natural product-derived drugs used clinically for colorectal cancer treatment. Furthermore, natural products of marine origin are also discussed for their enormous potential to serve as the candidate drugs. Notably, we generalize the experiment-based molecular mechanisms and the regulatory networks whereby natural products exert anticancer effects on cell proliferation, metastasis, apoptosis, autophagy, and angiogenesis.