FSHD is a severe muscle disorder resulting from aberrant DUX4 mRNA expression in skeletal muscle, which affects expression of downstream genes known as the DUX4 transcriptome (D4T), leading to progressive myofiber loss and debilitating weakness. We leveraged the FORCE delivery platform to develop DYNE-302, a Fab-drug conjugate targeting the human transferrin 1 receptor (TfR1) covalently attached to an siRNA payload that is highly specific for the DUX4 transcript that drives disease progression in muscle. DYNE-302 demonstrated high in vitro potency in FSHD patient-derived myotubes. To determine the in vivo efficacy of DYNE-302, we crossed mice expressing human TfR1 (hTfR1) with transgenics that express tamoxifen-inducible human DUX4 (iFLExD). The resulting hTfR1/iFLExD compound transgenic mice develop a slowly progressive myopathy due to sporadic, spontaneous DUX4 expression, or an acute myopathy after tamoxifen-induced DUX4 activation that causes loss of muscle function. A single intravenous dose of DYNE-302 produced a robust D4T inhibition that lasted up to 3 months and improved myofiber pathology. Moreover, DYNE-302 completely prevented the loss of muscle function in tamoxifen-induced hTfR1/iFLExD mice. Our data provide the preclinical foundation for the development of DYNE-302 as a therapy to treat FSHD.