Background and Objectives: The post-mortem diagnosis of hypothermia is challenging in forensics. The aim of our study was to detect the kidney and heart histopathological changes that occurred in a group of hypothermia-related fatalities. Materials and Methods: The cohort included 107 cases identified in the database of our department between 2007 and 2021, which have been associated with extreme cold stress. Demographic and clinicopathological data were collected from the medico-legal reports. Archived tissue samples were evaluated to identify the histopathological features, in routine haematoxylin-eosin (H&E), Periodic acid-Schiff (PAS), and Masson’s trichrome stainings, while cardiac sirtuin1 (SIRT1) and renal ubiquitin (Ub) immunostaining have been performed. Results: The majority of cases exposed to low temperatures were males (76%) from rural regions (68.2%) during the cold season. Paradoxical undressing was documented in 9.3% of cases. The common comorbidities included alcoholism (50.5%), neuropsychiatric diseases (10.3%), diabetes mellitus (3.7%), and lung tuberculosis (4.7%). The microscopic heart exam revealed areas of myocardial degeneration (100%), contraction bands (95.3%), fatty change (13.1%) and focal wavy contractile myocardial cells. Basal vacuolisation of renal tubular epithelial cells (Armanni-Ebstein lesions) (21.5%), focal tubular necrosis (7.5%), tubular renal cysts (7.5%), interstitial haemorrhages (5.6%), diabetic kidney disease (3.7%), background benign nephroangiosclerosis (42.1%), variable thickening of tubules and corpuscles basement membranes, capsular space amorphous material, and intratubular casts were identified in kidney tissue samples. Myocardial cells displayed SIRT1 weak expression, with a loss of immunopositivity correlated with areas with contraction bands, while a variable Ub expression was observed in renal corpuscles capsules, proximal, distal, and collecting renal tubules, Henle’s loops, urothelium, and intratubular casts. Conclusions: In the context of the current concept that death associated with hypothermia is still a diagnosis of exclusion, our findings suggest that the microscopic exam provides relevant data that support the diagnosis of hypothermia-related fatalities in appropriate circumstances of death. A deeper insight into the histopathologic findings in hypothermic patients may lead to new therapeutic approaches in these cases.