Harmine, a naturally occurring β-carboline alkaloid isolated primarily from Peganum harmala, has emerged as a promising anticancer compound based on extensive preclinical evidence. Studies demonstrate that harmine exerts antitumor effects across multiple malignancies, including breast, lung, colorectal, gastric, pancreatic, ovarian, and brain cancers. These effects are mediated through the modulation of diverse cellular and molecular mechanisms, such as inhibition of cell proliferation, induction of apoptosis and autophagy, suppression of epithelial–mesenchymal transition, inhibition of angiogenesis, and regulation of oncogenic signaling pathways including PI3K/AKT, p53, and Hippo signaling. Recent findings further suggest that harmine may influence components of the tumor microenvironment, thereby extending its antitumor activity beyond direct cancer cell targeting. Despite these encouraging results, clinical translation of harmine remains limited due to challenges including central nervous system toxicity, poor solubility, and insufficient pharmacokinetic characterization. This review critically evaluates the current evidence on the antitumor mechanisms of harmine, highlights key translational barriers, and discusses future strategies to facilitate its development toward clinical oncology.