Background: The concept of hope is an important theme in chronic illness and palliative care and has been associated with increased psycho-spiritual well-being and quality of life. Psycho-spiritual interventions have been described in this population, but no systematic review of hope-enhancing interventions or hopelessness-reducing interventions has been conducted for persons with palliative care diseases. Aim: To describe and assess the effectiveness of interventions in palliative care that measure hope and/or hopelessness as an outcome. Design: This systematic review and meta-analysis was pre-registered (Prospero ID: CRD42019119956). Data sources: Electronic databases, journals, and references were searched. We used the Cochrane criteria to assess the risk of bias within studies. Results: Thirty-five studies (24 randomized controlled trials, 5 quasi-experimental, 6 pre-post studies) involving a total of 3296 palliative care patients were included. Compared with usual/standard cancer care alone, interventions significantly increased hope levels at a medium effect size (g = 0.61, 95% confidence interval (CI) = 0.28–0.93) but did not significantly reduce hopelessness (g = −0.08, 95% CI = −0.18 to 0.02). It was found that interventions significantly increase spirituality (g = 0.70, 95% CI = 0.02–1.37) and decrease depression (g = −0.29, 95% CI = −0.51 to −0.07), but had no significant effect over anxiety, quality of life, and symptom burden. Overall, quality of evidence across the included studies was rated as low. Conclusions: Evidence suggests that interventions can be effective in increasing hope in palliative care patients.