This chapter provides a new perspective on the pathophysiological mechanisms contributing to the development of neuropsychiatric symptoms in the context of metabolic syndrome (MetS). The authors propose that alterations in mood and cognition occurring in MetS patients may reflect the neural consequences of some molecular and cellular events that play a pivotal role in the evolution of the disease. The chapter concentrates on the hypothesis that inflammation may contribute to the development of clinical signs of neuropsychiatric symptoms reported in MetS patients. The authors show that the neuroinflammation, particularly in the hippocampus, parallels the severity of MetS symptoms and is associated with development of mood and cognitive alterations. These findings may prove valuable for introducing new pharmacological and/or nutritional strategies to treat neuropsychiatric complications associated with MetS.