Multiple Sclerosis (MS) is a chronic disabling neuroinflammatory disease. Psychiatric manifestations have a high prevalence in MS patients and may worsen the illness progression and the patients’ quality of life (QoL). Depression is a highly prevalent condition in MS patients, associated with poorer adherence to treatment, decreased functional status and QoL, and increased suicide risk. Diagnosis and treatment of this disorder is challenging because of symptom overlap. Other prevalent psychiatric comorbidities are anxiety disorders, bipolar disorder, psychotic disorders, substance misuse and personality disorders. As the illness progresses, personality changes can happen, as well as affect abnormalities. Cognitive changes occur frequently in MS patients, and affect features like processing speed, attention, learning, memory, visual spatial capabilities, and some language deficits. Disease-modifying treatments may reduce cognitive impairment because of their container action on the brain’s lesion burden. Other QoL determinants such as fatigue, pain, sexual dysfunction, exercise, resilience and social support should be taken into account, in order to promote the individuals’ well-being. Further studies are needed in order to elucidate the effectiveness of pharmacotherapy and more neuroimaging studies are required to clarify the relationship between structural changes and psychiatric comorbidities.