Introduction: During its life cycle, malaria parasite has to traverse successfully through widely diverse environmental milieu of mosquito mid gut, RBC cytosol and human circulatory system where it is exposed to dramatic changes of extracellular milieu in terms of pH, osmolarity and ionic constituents. Therefore, the aim of this study was to examine the possible changes in the cations (Na+, K+, Mg2+, Ca2+, Cu2+ and Zn2+) in patients of malaria. Methods: Blood samples were collected in EDTA bulb at the time of admission (day-1) and on third day (day-3). The samples were analyzed within 24 hours of collection. Plasma sodium and potassium were measured by flame photometry and calcium, magnesium, copper, and zinc were measured by end point kit method. Results: The mean levels of plasma sodium, magnesium, calcium and zinc in the patients of malaria were significantly reduced (P<0.001) as compared to those in the control group. The levels of potassium and copper are significantly increased (P<0.001) in the malaria patients as compared to those in the control group. In the follow up study, the same parameters were studied in patients after antimalarial treatment and antimalarial + antioxidant treatment day-3. The levels of cations were reversed in the plasma. Conclusion: It concluded that the antimalarial drug regimen must be supported by antioxidants and trace elements supplementation to avoid grave penalty of reactive oxygen species and cations imbalance and also to improve the status of deviated biochemical parameters towards normalcy.