Accessible summary: What is known on the subject?: Understanding what strategies individuals use to cope with serious mental illness is vital for enhancing their quality of life, mental well‐being and recovery, and effective use of services;An episode of homelessness can be a profoundly disruptive event that often leads to chronic stress, social isolation, a negative belief about oneself and restricted access to care, among other adverse experiences; What the paper adds to existing knowledge?: In contrast to existing reviews of qualitative research focusing on escaping homelessness, managing problem substance use and growing resilience, the current review offers an in‐depth, interpretive account of coping with serious mental illness during an episode of homelessness;This paper integrates evidence showing the diverse and intricate processes via which homelessness can impede an individual's ability to successfully cope with life stressors and with chronic mental illness;Despite experiencing severe social disadvantage, many individuals demonstrate positive adaptation and coping, and even personal growth; What are the implications for practice?: It is important to be aware of the many ways in which coping with serious mental illness can be influenced by adverse environmental factors such as poverty, homelessness, traumatic life experiences and institutional discrimination;Nursing practice should recognize that coping efforts by individuals facing multiple forms of social disadvantage may be shaped by acute adverse life events and institutional interactions, as well as by the stresses and strains of living on the streets;Nursing practice should focus not only on reducing clients' mental illness symptoms and facilitating positive coping behaviours, but also on helping create the conditions that aid clients in leveraging inner resources for personal growth and constructive meaning‐making. Introduction: An evidence gap persists concerning the impact of extreme socio‐structural disadvantage, such as homelessness, on the nature and effectiveness of coping with severe mental illness (SMI). While existing reviews of qualitative research into homelessness have focused on processes such as escaping homelessness and managing concurrent problem substance use, as well as on the experiences of specific vulnerable groups such as women and youth, no analogical review has been dedicated to understanding the management of SMI during an episode of homelessness. Aim/Question: A qualitative metasynthesis of first‐person accounts was conducted to understand how individuals cope with SMI when experiencing homelessness. Method: The systematic search strategy yielded 481 potentially eligible sources. Following the team‐based full‐text screening and the two‐tiered quality appraisal, 14 studies involving 377 participants with lived experience were synthesized following Noblit and Hare's metaethnographic method. Results: Seven third‐order concepts were derived capturing the complex nature and processual character of coping, as well as the web of contextual influences upon coping strategies. The resultant line‐of‐argument synthesis reveals the dialectical relationship between the two higher‐order constructs—"the continuum of coping" and "the assemblage of disadvantage." Discussion: Despite the profoundly adverse impacts of biographical and socio‐structural conditions, many individuals mobilized internal and external resources to enable various coping processes. Coping in the context of multiple disadvantage is not a monolith but rather a multidimensional, contingent and fluid phenomenon. Implications for practice: Nursing practice should espouse a humanizing, structurally competent, and strength‐ and meaning‐oriented approach in order to meet the complex and multifaceted needs of such multiply disadvantaged persons. [ABSTRACT FROM AUTHOR]