Objective This study aimed to investigate the mediation effect of depressive symptoms on the relationship between white matter hyperintensities and the basic activities of daily living (BADL) using an integrated approach to overcome the limitations of previous studies and examine the relationship among the three variables simultaneously. Methods We performed structural equation modeling using cross-sectional data from 497 Alzheimer’s disease (AD), AD with small vessel disease, and subcortical ischemic vascular dementia patients enrolled in the Clinical Research for Dementia of South Korea registry who were diagnosed with mild-to-moderate dementia. Periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) were visualized separately at baseline using magnetic resonance imaging. Depressive symptoms were assessed using the Korean Form of the Geriatric Depression Scale at the follow-up assessment conducted after 1 year. BADL were assessed using the Barthel Index at the follow-up assessment conducted after 2 years. Results The direct and indirect effects of DWMHs on the BADL as mediated via depression were significant. However, neither the direct effect of PWMHs on the BADL nor the indirect effect of PWMHs on the BADL via depression were significant. Conclusion This study presented a mediation model that included a longitudinal developmental pathway from DWMHs to deterioration in the BADL mediated via depressive symptoms. Moreover, the mediation model of depressive symptoms could not be applied to the longitudinal developmental pathway from DWMHs to the deterioration in BADL.