Background: Chronic obstructive pulmonary disease (COPD) imposes tremendous challenges for both patients and informal caregivers. Caregivers are key players in the management of COPD. Recently, COVID-19 further increased reliance on informal caregivers who urgently need specific support. Objectives: This systematic literature review aimed to systematically describe the content and explore the effects of interventions to support informal caregivers of people with COPD. Methods: A mixed-methods systematic review was conducted. PubMed, Scopus, Web of Science, and EBSCO were searched. Studies implementing interventions supporting informal caregivers of people with COPD were included. Data were extracted and analysed in outcome domains and categories using framework analysis. Results: Twenty (14 quantitative, 4 mixed-methods, and 2 qualitative) studies were included. Informal caregivers were mainly female (86%). Caregiving context was poorly/never described. Interventions included patient-caregiver dyads and never caregivers only. Informal caregivers were invited to participate if available. Interventions were delivered across all COPD phases (acute/stable/advanced) and settings (inpatient/outpatient/home), with a wide range of total length, frequency, and duration of sessions. All included education about the disease and its management. Discharge/action plans (n = 12); adherence to therapy and healthy lifestyles (n = 9); and family concerns and psychosocial issues (n = 7) were also commonly addressed. Only 9 (45%) studies reported caregiver-related outcomes, and overall positive effects were observed in 7/9 outcome domains, using a high variety of qualitative and qualitative methods. Often categories were addressed but not assessed. Conclusion: Interventions have a narrow scope (i.e., education) and have not been specifically designed to support informal caregivers. Current evidence showed positive effects, but high methodological heterogeneity exists. Future studies need to explore caregiver-tailored, taking into consideration gender differences; multicomponent; and flexibly administered interventions to effectively support COPD caregivers.