Clinicians have found that fasting was frequently accompanied by an increased level of vigilance and a mood improvement, a subjective feeling of well-being, and sometimes of euphoria. Therapeutic fasting, following an established protocol, is safe and well tolerated. We aim in this article to explore the biological mechanisms activated during fasting that could have an effect on brain function with particular focus on mood (we do not discuss here the mechanisms regulating eating behavior) and to provide a comprehensive review on the potential positive impact of therapeutic fasting on mood. We explored Medline, Web of Science and PsycInfo according to the PRISMA criteria (Preferred Reporting Items for Systematic reviews and Meta-Analysis). The initial research paradigm was: [(fasting OR caloric restriction) AND (mental health OR depressive disorders OR mood OR anxiety)]. Many neurobiological mechanisms have been proposed to explain fasting effects on mood, such as changes in neurotransmitters, quality of sleep, and synthesis of neurotrophic factors. Many clinical observations relate an early (between day 2 and day 7) effect of fasting on depressive symptoms with an improvement in mood, alertness and a sense of tranquility reported by patients. The persistence of mood improvement over time remains to be determined.