Objective: Demoralisation is a state of poor coping characterised by low morale, hopelessness, subjective incompetence, and loss of meaning and purpose in life. While studied extensively in oncology and palliative care, there has been recent exploration in broader medical and mental health settings. The aim was to investigate the prevalence of demoralisation and associated sociodemographic and psychological factors across these clinical settings. Method: Six electronic databases were used to locate articles from January 2014 to March 2020. A pre-publication update of non-oncology populations was completed in September 2021. The review has been reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled prevalence of demoralisation was determined through % prevalence and mean demoralisation score; this was synthesised through meta-analysis of single means to determine pooled mean prevalence of Demoralisation Scale scores using the ‘R’ statistical software. Results: Demoralisation has been examined in 52 studies ( n = 11,670) and found to be prevalent in 24–35% of oncology and non-oncology, including mental health, populations. The mean score on the Demoralisation Scale was 24.3 (95% confidence interval, CI = [21.3, 27.3]). There was evidence of divergent validity in addition to significant comorbidity between depression, demoralisation and suicidal ideation. Burdensome physical symptoms, and psychological and demographic factors are strongly correlated with demoralisation. Conclusion: There remains a need to recognise demoralisation in various clinical and cultural settings and to strongly consider its inclusion as a ‘specifier’ within formal nosological systems for adjustment and depressive disorders. This is important to initiate targeted interventions and prevent significant morbidity.