Objective: Compassion-based interventions show promise in enhancing well-being and reducing distress, but little is known about their applications for people with long-term physical conditions. This study explores compassion-based interventions for this population: what are their differing elements (content, structure, tailoring, use of technology), feasibility and acceptability, effects and experienced benefits? Design: A mixed-methods systematic review was conducted. Four bibliographic databases were searched without study design restrictions. Meta-synthesis was used to integrate quantitative results of effects and qualitative results of experienced benefits. Results: Twenty studies met the inclusion criteria. Most studies targeted people with cancer or persistent pain. Interventions were either comprehensive with 6–12 face-to-face sessions, or brief based on a single compassion exercise. Feasibility and accessibility were highly rated by participants. Amongst a plethora of outcomes, reductions in depression and anxiety were the most common findings. Our qualitative synthesis yielded experienced benefits of (1) acceptance of the condition; (2) improved emotion regulation skills; (3) reduced feelings of isolation. There was minimal overlap between quantitative and qualitative outcomes. Conclusion: While the field is still in its infancy, this review highlights the potential benefits of compassion-based interventions for people with long-term physical conditions and discusses recommendations for further intervention research and development.