Tripartite motif-containing protein 13 (TRIM13) is a crucial member of the TRIM protein family, distinguished by its unique transmembrane domain that anchors it to the endoplasmic reticulum (ER). As an E3 ubiquitin ligase, TRIM13 influences multiple key signaling pathways through ubiquitination regulation, playing significant roles in modulating ER function, immune responses, metabolic disorders, inflammatory diseases, and tumor suppression. TRIM13 possesses the common RING, B-box, and coiled-coil domains of the TRIM family, along with its distinctive transmembrane domain. Its E3 ubiquitin ligase activity serves as the structural basis for its diverse biological functions. TRIM13 acts as a non-canonical ER-phagy receptor to participate in regulating ER stress responses, recruiting LC3 through interaction with SQSTM1/p62 to initiate autophagy-mediated degradation of damaged ER, which is crucial for maintaining ER homeostasis and cellular function under stress conditions. TRIM13 is involved in inflammatory and antiviral immune responses by modulating key molecules in signaling pathways such as MDA5, NF-κB, and STING, highlighting its potential in regulating innate immunity and inflammatory responses. TRIM13 is associated with various pathological conditions, particularly in cancer and metabolic diseases. In multiple cancers, including non-small cell lung cancer, hepatocellular carcinoma, and acute myeloid leukemia, TRIM13 exhibits tumor-suppressive effects, with its expression levels closely associated with patient prognosis, suggesting its potential as a biomarker or therapeutic target in oncology. In diabetic nephropathy, TRIM13 improves renal function by promoting CHOP ubiquitination and inhibiting interstitial collagen synthesis, demonstrating its protective role in kidney disease. In atherosclerosis, TRIM13 is involved in regulating cholesterol metabolism and inflammatory pathways, indicating its significance in cardiovascular disorders. Recent studies have also implicated TRIM13 in neurodegenerative disorders and metabolic syndromes, with its role in regulating protein quality control and ER stress responses, suggesting potential involvement in diseases characterized by protein misfolding and aggregation, such as Alzheimer’s and Parkinson’s diseases. Additionally, TRIM13’s participation in lipid metabolism and insulin signaling pathways points to its possible influence on obesity and diabetes. Despite significant advancements in TRIM13 research, the precise molecular mechanisms underlying its functions in various physiological and pathological processes remain to be elucidated. In this article, we review the structural characteristics and functions of TRIM13 protein, with particular emphasis on its roles in ER-phagy, inflammatory responses, and tumor suppression, as well as its potential significance in various diseases. Future studies should focus on revealing the specific core mechanisms of TRIM13 function and exploring its unique role in ER function regulation. A deeper understanding of TRIM13 protein and its regulatory mechanisms in development of diseases may provide novel targets and strategies for disease diagnosis and treatment.