Objective Establishing a transgenic mouse model for facioscapulohumeral muscular dystrophy (FSHD) using Myf6-CreERT2 mice and FLExDUX4 mice. And using tamoxifen induction to construct a mouse model of FSHD disease. Methods The dual transgenic mice (M6D4/+), were generated by crossbreeding Myf6-CreERT2 hemizygous mice with FLExDUX4 hemizygous mice, with full length DUX4 (DUX4-fl) expression induced by tamoxifen starting at 3 weeks of age. At the age of 9 weeks, the disease model was evaluated through experiments such as changes in body weight, four-limb strength, inverted screen test, skeletal muscle weight ratio, H E staining, Picrosirius Red staining and immunofluorescence of skeletal muscle paraffin section staining, quantitative real-time PCR, and RNA-seq of skeletal muscle. Results The dual transgenic heterozygous mice (M6D4/+) were successfully obtained. At 9 weeks, these mice exhibited significant physiological and pathological changes, including delayed weight gain, reduced four-limb strength and endurance, decreased skeletal muscle weight ratio, increases in centrally nucleated muscle fibers and fibrosis. RT-PCR revealed that the expression of DUX4 and its targeted genes were significantly upregulated in skeletal muscle. RNA-seq results revealed upregulation of immune regulation, interleukin-6, and tumor necrosis factor related genes, while downregulation of skeletal muscle development and differentiation related genes. Conclusion M6D4/+ mice effectively simulated the skeletal muscle phenotype of FSHD and are a good animal model for FSHD, which can be used for research on the pathogenesis, intervention, and treatment of FSHD.