Paneth cells (PCs) are specialized epithelial cells located at the base of the crypts of Lieberkühn in the small intestine and colon, that have been occasionally identified in colorectal adenomas and adenocarcinomas. Their presence in these lesions has raised questions regarding their role in colorectal neoplasia and their potential association with adenoma burden. To understand their potential role in carcinogenesis, we conducted an extensive review of the available literature on PubMed, focusing on the occurrence, molecular mechanisms, and implications of Paneth cells in neoplastic lesions of the colorectum. This review synthesizes current findings and discusses the potential of Paneth cells as diagnostic biomarkers and therapeutic targets in colorectal cancer.