Emerging evidence from observational studies suggests that lifestyle modifications, particularly moderate-intensity exercise, may confer neuroprotective benefits against dementia, potentially by enhancing brain resistance through clearance mechanisms. Using light-sheet fluorescence microscopy (LSFM) with tissue clearing, we investigated the role of voluntary swimming in ameliorating β-amyloid pathology in a transgenic Alzheimer's disease (AD) mouse model. Twenty 52-week-old hAPPsw mice were randomly divided into a 5-week voluntary swimming intervention group and a control group (each = 10). Each session included a 10-min swim followed by a 10-min rest, escalating from one session per day in the first week to three sessions per day by the fifth week. The excised brains were prepared using tissue-clearing and volume immunostaining with thioflavin-S for β-amyloid. For LSFM imaging, the individual plaque area and volume, total plaque load, and morphological parameters were quantified via an Imaris-based three-dimensional (3D) volumetric surface model. Visual comparison revealed that the intervention group presented significantly lower β-amyloid accumulation. The total surface volume of β-amyloid accumulation in the intervention group was significantly lower than that of the control group (intervention, 122,180,948 μm [105,854,660-169,063,081]; control, 167,201,016 μm [139,367,765-193,535,450]; = 0.043). There were no significant differences in the morphological parameters, such as ellipticity and sphericity. Our LSFM study demonstrated notable reductions in β-amyloid, as evidenced by a decrease in total surface volume, in 52-week-old transgenic mice after a 5-week structured swimming program, supporting the notion that even in advanced AD stages, leisure-time voluntary swimming serves as an efficacious intervention for augmenting resistance to pathology.