Metabolic syndrome has been associated in many studies with working in shifts. Even if the mechanistic details are not fully understood, forced sleep deprivation and exposure to light, as happens during night shifts, or irregular schedules with late or very early onset of the working program, lead to a sleep–wake rhythm misalignment, metabolic dysregulation and oxidative stress. The cyclic melatonin secretion is regulated by the hypothalamic suprachiasmatic nuclei and light exposure. At a central level, melatonin promotes sleep and inhibits wake-signals. Beside this role, melatonin acts as an antioxidant and influences the functionality of the cardiovascular system and of different metabolic processes. This review presents data about the influence of night shifts on melatonin secretion and oxidative stress. Assembling data from epidemiological, experimental and clinical studies contributes to a better understanding of the pathological links between chronodisruption and the metabolic syndrome related to working in shifts.