Objective To establish a transgenic mouse model of facioscapulohumeral muscular dystrophy (FSHD) using tamoxifen induction and Myf6-CreERT2 and FLExDUX4 mice. Methods Dual transgenic (M6D4/+) mice were generated by crossbreeding Myf6-CreERT2 hemizygous and FLExDUX4 hemizygous mice. Full length DUX4 (DUX4-fl) expression was induced by tamoxifen starting at 3 weeks old. The disease model was evaluated at 9 weeks old by assessing changes in body mass, four-limb strength, inverted screen test, skeletal muscle weight ratio, hematoxylin/eosin, Picrosirius Red, and immunofluorescent staining of skeletal muscle paraffin sections, quantitative real-time polymerase chain reaction (RT-PCR), and RNA-sequencing (RNA-seq) of skeletal muscle. Results Dual transgenic heterozygous mice (M6D4/+) were successfully obtained. These mice exhibited significant physiological and pathological changes at 9 weeks, including delayed weight gain, reduced four-limb strength and endurance, decreased skeletal muscle weight ratio, and increases in centrally nucleated muscle fibers and fibrosis. Expression levels of DUX4 and its targeted genes were significantly up-regulated in skeletal muscle, as demonstrated by RT-PCR. RNA-seq revealed up-regulation of immune regulation-, interleukin-6, and tumor necrosis factor-related genes and down-regulation of skeletal muscle development- and differentiation-related genes. Conclusions M6D4/+ mice effectively simulated the skeletal muscle phenotype of FSHD and thus provide a good animal model for research into the pathogenesis, intervention, and treatment of FSHD.