<p>This study aims to investigate the potential changes of interactive relationships among neurofluid metrics in cerebral small vessel disease (CSVD). Forty-one CSVD patients and 34 elderly controls were consecutively enrolled. Neurofluid metrics, including normalized cerebral blood flow (nCBF) of gray matter (GM) and white matter (WM), diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and cerebrospinal fluid (CSF) volume of ventricles, were assessed using arterial spin labeling, diffusion tensor imaging, and volumetric measurements. Multivariate linear regression with interaction analysis was performed on neurofluid metrics between the CSVD group and the control group. Linear regression analysis for white matter hyperintensities (WMHs) volume was conducted. Multiple mediation analysis was performed to investigate potential mediation effects of neurofluid metrics on cognitive function. The interactive correlations in the CSVD group between DTI-ALPS index and nCBF of GM (<i>P</i> &lt; 0.001), DTI-ALPS and nCBF of WM (<i>P</i> = 0.002), CSF volume of ventricles and DTI-ALPS (<i>P</i> &lt; 0.001), CSF volume of ventricles and nCBF of GM (<i>P</i> = 0.025), CSF volume of ventricles and nCBF of WM (<i>P</i> = 0.008) were significantly different from those in the control group. The nCBF of GM was significantly correlated with WMHs volume when other neurofluid metrics were controlled (<i>P</i> = 0.001). DTI-ALPS index, the nCBF of GM and WM significantly mediated the relationship between CSVD status and cognitive function. Disruption of neurofluid status may play an important role in the cognitive impairment of CSVD.</p>