Background: Ovocystatin is marked by structural and biological similarities to human cystatin C, which plays an important role in the course of neurodegenerative diseases. Recently, it has been shown that ovocystatin might prevent aging-related cognitive impairment in rats and reduce memory decline in an APP/PS1 mice model. Thus, this study aimed to assess the effect of ovocystatin on histopathological changes in APP/PS1 mice. Materials and methods: Ovocystatin was administered intraperitoneally for four weeks (40 μg/mouse) to 35-weeks-old transgenic (AD, n = 14) and wild type (NCAR, n = 15) mice (stock B6C3-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax). A histopathological evaluation comprised antibodies directed against β-amyloid (1:400, SIG-39320-1000, Covance) and Tau (1:4000, AHB0042, Invitrogen). Three regions of the hippocampus— the dentate gyrus (DG) and the cornu ammonis (CA1 and CA3)—were analyzed by immunohistochemistry in each animal. All differences are expressed as percentage relative to the control group. Results: The main results showed that the percentage of immunoreactive area of β-amyloid, tau protein deposits in APP/PS1+ovCYS was decreased in DG, CA1, and CA3 regions compared with the APP/PS1 control, respectively (p < 0.05). Conclusions: Ovocystatin caused significant changes in the expression pattern of all investigated proteins in hippocampal tissues both in APP/PS1 and NCAR mice.