Major depressive disorder is significantly increased in patients following acute coronary syndrome resulting in twofold increased mortality compared with patients without depression. The depression diagnosis is often missed leading to considerable undertreatment. This systematic review assesses the current evidence of primary prophylactic treatment of depression in patients after acute coronary syndrome. The study protocol was prospectively registered at PROSPERO (registration number CRD42015025587). A systematic review were conducted and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, PsychINFO, CINAHL, and Cochran Library was searched. Two independent reviewers screened the records. The inclusion criteria were randomized controlled trials on adult patients with acute coronary syndrome treated prophylactically with an antidepressant intervention of any kind. A validated assessment tool should measure depression and depressive symptoms. Languages were limited to articles written in English. Six articles were included. Four studies utilized different components of case and disease management, health coaching, or relaxational audiotapes as intervention compared with usual care or with no formal program of rehabilitation. None of the studies showed any significant prophylactic effect against depression. One study with a program of health education and counselling and another study with a pharmacological antidepressant showed significant prophylactic effect on depression and depressive symptoms. All six included studies were associated with high risk of bias. There is not strong evidence of the effects of any type of routine antidepressant prophylaxis in patients following acute coronary syndrome. Further high quality studies are warranted.