Acellular mucin refers to pools of mucin without epithelial component, oftentimes harboring inflammatory cells. Acellular mucin can be observed in both neoplastic and non-neoplastic lower gastrointestinal (GI) conditions. While mucinous neoplasms are classified and staged using established guidelines, interobserver variability occurs when acellular mucin pools are encountered, leading to inconsistent interpretation and staging. In particular, acellular mucin found in regional lymph nodes of colorectal adenocarcinoma patients who have not received treatment presents a diagnostic challenge, as its prognostic implication is not clearly defined. Acellular mucin is also commonly seen in treated colorectal adenocarcinoma, post neoadjuvant therapy. Although acellular mucin is not counted toward T or N staging in this setting, variation in how pathologists report and stage these cases persists. Acellular mucin can also be seen in non-neoplastic specimens, such as those from interval appendectomies, appendiceal diverticula, colonic diverticulitis, volvulus, and Crohn's disease where it may mimic a neoplastic lesion. Acellular mucin in this setting is often a byproduct of inflammation, increased luminal pressure, and mural defect. This review highlights the clinical relevance and diagnostic complexity of acellular mucin in pathologic conditions of the lower GI tract. Further studies are needed to clarify its prognostic value and develop standardized guidelines.