Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is a complex neuromuscular disorder driven by DUX4 misexpression, requiring robust preclinical models to elucidate disease progression and evaluate therapeutic interventions. The FLExDUX4 mouse model, engineered to mimic FSHD pathology through inducible DUX4 expression, offers a unique platform for studying disease mechanisms using either the tamoxifen-inducible model that regulates DUX4 expression to accelerates disease progression or the uninduced “leaky” model. Methods: The current study evaluated the natural history of the FLExDUX4 mouse model using standard motor function assessments (wire hang and grip strength), muscle contractility, and novel endpoints including gait analysis (DigiGait) and in vivo multispectral optoacoustic tomography (MSOT). FLExDUX4 mice (Het;Hemi FSHD vs. ACTA-MCM and Het;NCAR wild-type controls) and the D2.mdx model of DMD vs. DBA/2J controls were assessed. Results: Wire hang and Grip strength function were generally reduced in FSHD mice from 3 to 6 month timepoints, while D2.mdx were significantly reduced vs. DBA/2J control. Normalized muscle torque was significantly reduced in the Het;Hemi FSHD mice compared to Het;NCAR and ACTA MCM controls, and similarly reduced in D2.mdx versus DBA/2J in both sexes. Gait analysis revealed impaired gait in FSHD mice, most pronounced at 4 months, while gait parameters in the D2.mdx mice were unaltered. MSOT analysis showed no differences in hemoglobin (Hb) O2 or muscle O2 saturation (mSO2) saturation, however in tamoxifen-induced FSHD mice, mSO2 was reduced at baseline and increased with 100% vs. 21% O2 suggesting reduced muscle perfusion under normoxic conditions. Conclusion: These data show distinct parameters of muscle function and pathology in the FSHD FlexDux mice vs. the D2.mdx model of DMD. A complete analysis of the entire dataset including the 12-month timeline and histological analyses will provide a more comprehensive view of the phenotypic changes of the FLExDUX4 model.