The high fat diet (HFD) can trigger metabolic and cardiovascular diseases. Trypanosoma cruzi infection induces progressive inflammatory manifestations capable to affect the structure and the function of important organs such as the heart and liver. Here we aimed to investigate the effects of a HFD on the immune response and matrix metalloproteinase (MMP) activities during acute infection with the T. cruzi strain VL-10. The VL-10 strain has cardiac tropism and causes myocarditis in mice. Male C57BL/6 mice were treated with either: (i) regular diet (Reg) or (ii) HFD for 8 weeks, after which mice in each group were infected with T. cruzi. Mice were euthanized on day 30 after infection, and the liver and heart were subjected to histology and zymography to determine MMP-2 activities and plasma levels of IL-10, TNF, CCL2, and CCL5. T. cruzi-infected HFD animals had higher parasitemia, LDL and total cholesterol levels. Regardless of diet, plasma levels of all inflammatory mediators and cardiac MMP-2 activity were elevated in infected mice in contrast with the low plasma levels of leptin. HFD animals presented micro- and macrovesicular hepatic steatosis, while cardiac leukocyte infiltration was mainly detected in T. cruzi-infected mice. Our findings suggested that a HFD promotes higher circulating T. cruzi load and cardiac and liver immunopathogenesis in an experimental model using the VL-10 strain of the T. cruzi.