Understanding the pharmacokinetics of drug candidates of interest in the brain and evaluating drug delivery to the brain are important for developing drugs targeting the brain. Previously, we demonstrated that a CAG repeat-binding small molecule, naphthyridine-azaquinolone (NA), resulted in repeat contraction in mouse models of dentatorubral-pallidoluysian atrophy and Huntington's disease caused by aberrant expansion of CAG repeats. However, the intracerebral distribution and drug deliverability of NA remain unclear. Here, we report three-dimensional whole-brain imaging of an externally administered small molecule using tissue clearing and light sheet fluorescence microscopy (LSFM). We designed and synthesized an Alexa594-labeled NA derivative with a primary amine for whole-brain imaging (NA-Alexa594-NH2), revealing the intracerebral distribution of NA-Alexa594-NH2 after intraparenchymal and intracerebroventricular administrations by whole-brain imaging combined with tissue clearing and LSFM. We also clarified that intranasally administered NA-Alexa594-NH2 was delivered into the brain via multiple nose-to-brain pathways by tracking the time-dependent change in the intracerebral distribution. Whole-brain imaging of small molecules by tissue clearing and LSFM is useful for elucidating not only the intracerebral distribution but also the drug delivery pathways into the brain.