Alzheimer's disease (AD) is a primary neurodegenerative disorder associated with progressive memory impairment. Recent studies suggest that hypothermia may contribute to the development and exacerbation of AD. The aim of this study was to investigate the role of chronic hypothermia on spatial learning and memory performance as well as brain immunohistochemical (IHC) and molecular changes. Four groups of male rats were placed in cold water (3.5 ± 0.5 °C) once a day for 1, 3, 6, and 14 days, four other groups were placed in warm water (32 °C) as the control groups to eliminate the effect of swimming stress, and one more group which comprised intact animals that were kept in a normothermic situation and had no swimming stress. Twenty-four hours after the last intervention, spatial learning and memory were assessed, using the modified Morris water maze. After the behavioral test, the rats' brains were removed for IHC and Western blotting. The results showed that memory retrieval is impaired after 14 days of cold water-induced hypothermia (CWH) (P < 0.05). IHC showed the formation of beta-amyloid plaques after a 14-day CWH. The molecular changes demonstrated that a 14-day CWH induces tau hyperphosphorylation, apoptosis, and reduces COX-II expression. Therefore, chronic CWH, independent of forced swimming stress, impairs learning and memory through molecular mechanisms similar to those of AD. In conclusion, CWH may serve as an important model to assess the role of hypothermia in AD pathogenesis.