Mitochondrial activity is involved in different functions such as cell proliferation, metabolism, Adenosine triphosphate (ATP) generation, and cell death. Particularly, mitochondria play a major role in inflammatory signaling. They regulate the activation, differentiation, and survival of macrophages, while changes in oxidative metabolism alter polarization. Mitochondria are the main source of free radicals, and macrophages increase their oxidative stress levels when they are active. The enhancement of free radicals generation in the mitochondria can damage healthy cells, leading to inflammation. Thus, several diseases associated with an increase in mitochondrial oxidative stress can be associated with chronic inflammation. The intricate crosstalk of mitochondrial metabolism and the innate immune response is well-known. However, the therapeutical implication of metabolic reprogramming, modifying the metabolic niche, or targeting mitochondria in macrophages in specific inflammatory diseases is still unclear. Thus, the goal of this topic is to understand whether alterations of oxidative metabolism, the release of mitochondrial reactive oxygen species, mitochondrial membrane potential, as well as changes in mitochondrial metabolites regulate innate immunity. On one side, we aim to better understand the mitochondria-dependent regulation of the biology of macrophages. On the other hand, we focus on the study of oxidative metabolism in the inflammatory response associated with chronic diseases, but also under the presence of invading germs. The most recent advances in the topic will help to find new clinical interventions to treat acute and chronic inflammation.