Background: More than one in ten adults in the US are family caregivers, with cancer among the most common diagnoses of care recipients. Family caregivers of patients with advanced cancer often have poor quality of life (QOL) and mental health. We examined the effectiveness of interventions offering support for caregivers of patients with advanced cancer on caregiver QOL and mental health outcomes. Methods: We searched Ovid MEDLINE, EMBASE, Cochrane CENTRAL, and CINAHL databases from inception through 6/2021. Eligible studies reported on randomized controlled trials for adult caregivers of adult patients with advanced cancer. Meta-analysis was conducted for primary outcomes of QOL, physical well-being, mental well-being, anxiety, and depression, from baseline to follow-up of 1-3 months; secondary endpoints were these outcomes at 4-6 months and additional caregiver burden, self-efficacy, family functioning and bereavement outcomes. Random effects models were used to generate summary standardized mean differences (SMD). Meta-regression was conducted for primary outcomes that were significant for the intervention, assessing for mediation effect modification by caregiver sex and age of patient and caregiver. Type I error was 0.05. PROSPERO Registration: CRD42019136321. Results: Of 12,193 references identified, 56 articles reporting on 49 trials involving 8,554 caregivers were eligible for analysis; 16 (33%) targeted caregivers (mostly psychoeducational or problem-solving interventions), 19 (39%) patient-caregiver dyads (mostly counseling/therapy), and 14 (29%) patients and their families (mostly palliative care teams). At 1-3 month follow-up, interventions had a significant effect on overall QOL (SMD 0.24 (0.10 to 0.39), I2 = 52.0%), mental well-being (SMD 0.14 (0.02 to 0.25), I2 = 0.0%), anxiety (SMD 0.27 (0.06 to 0.49), I2 = 74.0%), and depression (SMD 0.34 (0.16 to 0.52), I2 = 64.4%), compared to standard care. At 1-3-month follow-up, a larger age difference (older patient and younger caregiver) was associated with a greater positive effect on QOL (p = 0.04) and depression (p = 0.02). In narrative synthesis, interventions demonstrated improvements in caregiver self-efficacy and grief. Conclusions: Interventions targeting caregivers, dyads, or patients and families led to improvements in caregiver QOL and mental health outcomes. These data support the routine provision of available interventions to support caregivers of patients with advanced cancer.