Coffee is one of the most popular beverages worldwide. Coffee contains bioactive compounds that affect the human body such as caffeine, caffeic acid, chlorogenic acids, trigonelline, diterpenes, and melanoidins. Some of them have demonstrated potential anticarcinogenic effects in animal models and in human cell cultures, and may play a protective role against colorectal cancer. Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the USA and other countries. Dietary patterns, as well as the consumption of beverages, may reduce the risk of CRC incidence. In this review, we focus on published epidemiological studies concerning the association of coffee consumption and the risk of development of colorectal cancer, and provide a description of selected biologically active compounds in coffee that have been investigated as potential cancer-combating compounds: Caffeine, caffeic acid (CA), chlorogenic acids (CGAs), and kahweol in relation to colorectal cancer progression in in vitro settings. We review the impact of these substances on proliferation, viability, invasiveness, and metastasis, as well as on susceptibility to chemo- and radiotherapy of colorectal cancer cell lines cultured in vitro.