The proto-oncogene LIM-domain only 2 (lmo2) was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia. Recently, the cytosolic localization of LMO2 was revealed in multiple epithelial tissues and a variety of solid tumors. However, the function of LMO2 in these epithelia and solid tumors remains largely unclear. The Wnt signaling pathway is a crucial determinant of development, and abnormalities in several key segments of this pathway contribute to oncogenesis. The current study demonstrated that LMO2 participates in the regulation of canonical Wnt signaling in the cytoplasm by binding to Dishevelled-1/2 (DVL-1/2) proteins. These interactions occurred at the PDZ domain of Dishevelled, and LMO2 subsequently attenuated the activation of the key factor β-catenin in the canonical Wnt signaling pathway. Meanwhile, significantly decreased expression of LMO2 was detected in breast and colorectal cancers, and the downregulation of LMO2 in these cells increased cell proliferation and reduced apoptosis. Taken together, the data in this study revealed a novel crosstalk between LMO2 and the Wnt signaling pathway during tumorigenesis and suggested that LMO2 might be a tumor suppressor in certain solid tumors, in contrast to its traditional oncogenic role in the hematopoietic system.