The recovery of a corpse from water raises an array of questions with no adequate answer, despite all signs that drowning cases could offer. This required other ancillary investigations such as; biochemical changes in different body fluids. Objectives: This work aimed at studying biochemical and electrolyte changes to differentiate true drowning from postmortem submersion in fresh and seawater using an experimental drowning model. Methods: Five groups of 8 adult male albino rats each were used, including anesthetically mechanically euthanized rats without exposure to submersion (as a control group), Group II: postmortem-submersion (PS) in freshwater, Group III: PS in saltwater, Group IV: truly drowned death (TDD) in freshwater, Group V: TDD in saltwater. Results: Certain markers significantly increased in the TDD of the saltwater compared to that of the freshwater group, such as sodium (Na), chloride (Cl), magnesium (Mg), calcium (Ca), tumor necrosis factor-α (TNF-α), creatine phosphokinase (CPK), triglycerides, total protein, albumin, strontium (Sr) and cardiac troponin (pericardial fluid and peripheral blood). The summation of Na+, K+, Cl levels, and Sr concentration significantly increased in TDD of the saltwater group compared to the other groups. On the other hand, some parameters like blood urea nitrogen (BUN), creatinine (Cr), atrial natriuretic peptide (ANP), and surfactant-associated protein (ASP-A) significantly increased in the TDD of the freshwater compared to those of the saltwater group. Conclusion: Serum electrolytes and biomarkers could serve as adjunct parameters in confirming drowning and differentiating between freshwater and saltwater drowning as well.