Atherosclerosis and aortic valve sclerosis are cardiovascular diseases with an increasing prevalence in western societies. Statins are widely applied in atherosclerosis therapy, whereas no pharmacological interventions are available for the treatment of aortic valve sclerosis. Therefore, valve replacement surgery to prevent acute heart failure is the only option for patients with severe aortic stenosis. Both atherosclerosis and aortic valve sclerosis are not simply the consequence of degenerative processes, but rather diseases driven by inflammatory processes in response to lipid-deposition in the blood vessel wall and the aortic valve, respectively. The p38 mitogen-activated protein kinase (MAPK) is involved in inflammatory signaling and activated in response to various intracellular and extracellular stimuli, including oxidative stress, cytokines, and growth factors, all of which are abundantly present in atherosclerotic and aortic valve sclerotic lesions. The responses generated by p38 MAPK signaling in different cell types present in the lesions are diverse and might support the progression of the diseases. This review summarizes experimental findings relating to p38 MAPK in atherosclerosis and aortic valve sclerosis and discusses potential functions of p38 MAPK in the diseases with the aim of clarifying its eligibility as a pharmacological target.