An excessive consumption of a high-fat diet (HFD) results in becoming overweight or obese, which triggers a chronic inflammatory condition that is associated with a high white blood cell count. Because of the potential for yerba mate (Ilex paraguariensis) (YM) to impact obesity, this study aimed to investigate the effects of YM consumption on the hematological response and on the production of interleukin (IL)-1 alpha, IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 by bone marrow cells from Wistar rats fed a HFD. Male Wistar rats were fed a control (CON) or HFD diet for twelve weeks. At the end of this period, the rats received YM (1 g/kg/day body weight) for 4 weeks. After euthanasia, hemograms and myelograms were evaluated, while the bone marrow cells were cultured in the presence or absence of lipopolysaccharide (LPS) to evaluate the production of IL-1 alpha, IL-6, TNF-alpha, and IL-10. The consumption of YM reduced the body weight, the body adiposity, and the cholesterol levels in HFD-fed rats. Bone marrow cells from the HFD group produced more IL-1 alpha, IL-6, and TNF-alpha, and less IL-10, when compared to cells from the control group, and YM consumption reduced the IL-1 alpha, IL-6, and TNF-alpha production by the cells. However, cells from the HFD rats that were stimulated with LPS increased their IL-1 alpha, IL-6, and TNF-alpha production, but YM consumption did not change this result. In summary, the consumption of YM affects the production of IL-1 alpha, IL-6, and TNF-alpha by bone marrow cells, promotes weight loss, decreases the number of white blood cells, and significantly improves serum cholesterol level in HFD-fed rats. However, the bone marrow cells from the HFD+YM-fed rats challenged with LPS did not show improvement in the inflammatory response compared to the cells from animals fed only a HFD that were also challenged with LPS.