Abstract: Coix seed is a commonly used medicinal and food-homologous traditional Chinese medicine in clinical practice. Its active ingredients, including lipids, polysaccharides, sterols, and flavonoids, have been demonstrated to possess definite antitumor potential. Based on the latest research evidence, this review systematically summarizes studies related to the antitumor effects of Coix seed. Focusing on the multi-component, multi-target, and multi-level characteristics of Coix seed active ingredients in regulating the tumor microenvironment, this review discusses their roles in modulating the immune microenvironment, influencing extracellular matrix remodeling, inducing lipid peroxidation and ferroptosis, regulating the gut microbiota–immune axis, and enhancing the efficacy while reducing the toxicity of radiotherapy and chemotherapy. This review aims to provide a theoretical reference for elucidating the pharmacodynamic material basis of Coix seed active ingredients and promoting their rational application in comprehensive cancer therapy.