Background: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality globally, with its incidence steadily rising due to increasing rates of chronic liver diseases. Systemic treatments, including targeted therapies, immunotherapy, and chemotherapy, play a critical role in extending survival and improving quality of life (QoL). This systematic review and meta-analysis aim to evaluate the efficacy of various systemic treatments for HCC while also examining their effects on QoL. Method: A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines using the PICO framework. Rigorous screening, data extraction, risk of bias assessment, and statistical analysis were performed to aims to evaluate the efficacy of various systemic treatments for HCC while also examining their effects on QoL. Results: A total of 88 articles were retrieved from online databases (PubMed, SagePub, Nature and Cochrane). After three rounds of screening, six articles directly relevant to the meta-analysis were selected for full-text reading and analysis. The pooled mean difference (MD) of 2.14 months (95% CI: [1.17, 3.10]) strongly supports the efficacy of systemic treatments in extending the survival of HCC patients. Conclusion: Management of HCC with systemic treatments demonstrates improved median overall survival. However, quality of life assessments show mixed results, highlighting the importance of considering both survival benefits and patient well-being. Adverse events can significantly impact QoL, underscoring the need for comprehensive treatment strategies that balance efficacy and manage side effects. Future research should prioritize patient centered outcomes and long-term safety.