There is an unmet need to reliably and non-invasively monitor disease progression in preclinical Huntington's disease (HD) models. As a marker of axonal damage, neurofilament light chain (NfL) has been suggested a marker for neurodegeneration. NfL concentrations in blood and CSF were recently shown to have prognostic value for clinical HD progression and brain atrophy. We therefore hypothesized that CSF and blood NfL concentrations could be useful preclinical HD markers, reflecting underlying pathology. To test our hypothesis we utilized the R6/2 mouse model of HD and measured NfL concentrations in CSF and serum using the ultrasensitive Single molecule array (Simoa) platform. In addition, we assessed HD mouse disease characteristics. We found robust increases of NfL in CSF and serum in R6/2 mice compared to wild-type littermates. CSF and serum concentrations of NfL were significantly correlated, suggesting similar marker potential of serum NfL. CSF and serum concentrations of NfL correlated with disease severity, as assessed by striatal volume and body weight loss. We here provide evidence that CSF and blood NfL concentrations can be used as accessible and reliable pre-clinical HD markers. This will be of potential use for monitoring HD mouse model disease progression and evaluating preclinical disease-modifying treatment response.