Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. Euphol, a triterpenoid alcohol derived from Euphorbia tirucalli , has demonstrated anti-tumor activity in various cancer cell lines; however, its effects in advanced preclinical models remain underexplored. Here, we aimed to investigate the biological and chemopreventive potential of euphol across multiple colorectal experimental systems. Euphol exposure significantly reduced cell viability and colony formation in a dose-dependent manner in a panel of commercial and primary CRC cell lines. In 3D mouse-derived organoids (MDOs), euphol decreased organoid viability while preserving immune cell populations (CD4 +, CD8 +, NK) in co-culture with murine splenocytes. Immunoblotting revealed no modulation of PKC isoforms phosphorylation. In vivo , euphol suppressed intestinal tumor development in the Apc ^LoxP/+ -Cdx2-Cre chemoprevention mice model and reduced tumor growth in PDX mice, without overt toxicity. Altogether, these findings highlight euphol as a promising candidate for both therapeutic and chemopreventive strategies against CRC, warranting further investigation in clinical settings.