The effectiveness of psychological interventions (PI) for malignant diseases is controversial. We aimed to investigate the effect of PI on survival and quality of life (QoL) in patients with cancer. We performed a systematic search of MEDLINE, Cochrane, and Embase databases to identify randomized controlled trials comparing PI to standard care (PROSPERO registration number CRD42021282327). Outcomes were overall survival (OS), recurrence-free survival (RFS), and different domains of QoL. Subgroup analysis was performed based on the provider-, type-, environment-, duration of intervention; cancer stage, and type. Pooled hazard ratios (HR) and standardized mean difference (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model. The OS and RFS did not differ significantly between the two groups (OS:HR = 0.97; CI 0.87–1.08; RFS:HR = 0.99; CI 0.84–1.16). However, there was significant improvement in the intervention group in all the analyzed domains of QoL; in the global (SMD = 0.65; CI 0.35–0.94), emotional (SMD = 0.64; CI 0.33–0.95), social (SMD = 0.32; CI 0.13–0.51) and physical (SMD = 0.33; CI 0.05–0.60) domains. The effect of PI on QoL was generally positive immediately, 12 and 24 weeks after intervention, but the effect decreased over time and was no longer found significant at 48 weeks. The results were better in the breast cancer group and early stages of cancer. PIs do not prolong survival, but they significantly improve the QoL of cancer patients. PI should be added as standard of care 3–4 times a year, at least for patients with early-stage cancer.