Objective: DiGeorge syndrome (22q11.2 deletion syndrome) is the most common chromosomal microdeletion disorder and is a multisystem developmental anomaly caused by the deletion of 22q11.2 chromosomal microdeletions. Transport and Golgi Organization protein 2 Homolog (TANGO2) is one of the genes located on 22q11.2 microdeletion fragment. Here, we generated TANGO2 knockout mice to elucidate its physiological function in mammals, and to explore whether TANGO2 is a candidate gene responsible for DiGeorge syndrome. Methods: The TANGO2 knockout mouse model was generated, and the knockout efficiency of the mouse model was detected by real-time quantitative PCR. The phenotype, growth and breeding of wild-type, TANGO2+/- and TANGO2-/- mice were observed and recorded. The morphological structures of heart and brain tissues in wild-type and knockout mice were observed through anatomic and histological analysis. Results: TANGO2 mRNA was expressed in the heart and brain of wild-type mice, but its expression level was substantially reduced in knockout mice. TANGO2 knockout mice could develop, survive and reproduce, and did not exhibit obvious phenotypic abnormalities. Histological analyses of the heart and brain showed no big differences between knockout mice and wild-type at birth and 6-month-old. Conclusion: TANGO2 knockout mice grow and reproduce normally and lack the phenotype associated with TANGO2-related disorders or DiGeorge syndrome in humans.