Background: Stigma toward mentally ill individuals acts as a barrier to accessing care and receiving treatment. Aim: To review current evidence pertaining to stigma toward mental illness in the Middle East in order to inform effective and sustainable interventions in this region. Methods: We conducted a systematic literature search using the PubMed database and evaluated all identified studies according to specific inclusion criteria. Results: Stigma toward individuals with mental illness does exist in the Middle East. Stigmatizing attitudes are particularly high toward culturally proscribed mental illnesses like alcohol abuse and lower for other disorders such as depression and psychosis. Conclusions: We propose the following initiatives to reduce stigma toward mental illness in the Middle East: (a) educate families to enable them to support their affected relatives, (b) increase cooperation between psychiatrists and faith healers and (c) educate young people in schools to increase their awareness and understanding of mental illnesses and to combat negative stereotypes.