Adequate responses to environmental stresses are essential for cell survival. The regulation of cellular energetics that involves mitochondrial energy production and oxidative stress is central in the process of stress adaptation and response. The p38α signalling pathway plays a key role in the response to stress stimuli by orchestrating multiple cellular processes. However, prolonged activation of the p38α pathway results in impaired cell proliferation and can lead to cell death. Here we use a system to specifically activate p38α signalling and show that sustained activation of this pathway suffices to induce important metabolic changes, including high dependence on glucose for cell survival, increased consumption of glutamine, enhanced respiration rate and elevated production of mitochondrial reactive oxygen species (ROS). Moreover, we provide evidence that increased production of mitochondrial superoxide as a consequence of elevated mitochondria activity, contributes to the p38α reduced cell survival triggered by sustained p38α activation. We also show that the p38α-activated kinase MAPKAPK2 (MK2) plays an important role orchestrating the observed metabolic changes. Our results illustrate a new function of p38α signalling in the regulation of cellular metabolism, which may lead to cell death upon persistent activation of the pathway.