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Among patients with advanced disease, meaning in life is thought to enhance well-being, promote coping and improve the tolerance of physical symptoms. It may also act as a buffer against depression and hopelessness. As yet, there has been no synthesis of meaning in life interventions in which contextual factors, procedures and outcomes are described and evaluated.To identify meaning in life interventions implemented in patients with advanced disease and to describe their context, mechanisms and outcomes.Systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and realist synthesis of meaning in life interventions using criteria from the Realist And Meta-narrative Evidence Syntheses: Evolving Standards project.The CINAHL, PsycINFO, PubMed and Web of Science databases were searched.A total of 12 articles were included in the systematic review, corresponding to nine different interventions. Five articles described randomized controlled trials, two were qualitative studies, two were commentaries or reflections, and there was one pre–post evaluation, one exploratory study and one description of a model of care. Analysis of context, mechanisms and outcomes configurations showed that a core component of all the interventions was the interpersonal encounter between patient and therapist, in which sources of meaning were explored and a sense of connectedness was re-established. Meaning in life interventions were associated with clinical benefits on measures of purpose-in-life, quality of life, spiritual well-being, self-efficacy, optimism, distress, hopelessness, anxiety, depression and wish to hasten death.This review provides an explanatory model of the contextual factors and mechanisms that may be involved in promoting meaning in life. These approaches could provide useful tools for relieving existential suffering at the end of life.