Abstract: Malaria is a parasitic disease which is common in tropical and subtropical regions of the world. Lipopolysaccharide (LPS) as an inducer and dexamethasone (DEX) as an inhibitor of the immune system are used in this study. The LPS and DEX effects on the level of nitric oxide (NO) of plasma, liver and spleen, hepatomegaly, splenomegaly, survival rate and the degree of parasitaemia on malaria infected mice were investigated. In this study, 24 outbred mice were randomly divided into 4 groups of 6 animals. Entire mice were infected by the murine malaria parasite Plasmodium berghei. Two groups of mice were selected as controls, which were injected with intraperitoneal (ip) injection of normal saline. The two DEX and LPS groups of mice had received concentrations of 4 and 1 mg kg–1 treatment respectively by 8 times ip injection every other day. Their body weight, survival rates and parasitaemia were monitored during the study. Finally, mice were euthanized by terminal anesthesia and cardiac puncture and the entire liver and spleen were removed for hepatosplenomegaly. Plasma and liver/spleen suspensions were assessed for immunobiochemical alterations of NO levels. The results indicated an increase in hepatomegaly of test group compared to control mice. The LPS mice represented splenomegaly more than DEX one. Nitric oxide in plasma, liver and spleen in both DEX and LPS group was changed, however, the only significant difference was observed in the liver of LPS. It is concluded that LPS and DEX can be applied as a standard and medically approved inducer and inhibitor of the immune system respectively, for experimental immunomodulation studies in animal models. In this study, LPS induced and DEX reduced immune responses in mice during malaria infection by alterations and manipulation of immunobiochemical factors via NO pathway. This may lead to an immunotherapy trial of malaria by control the pathophysiology and degree of parasitaemia in mouse model.