BACKGROUND: Despite the use of current standard therapy, the prognosis of patients with unresectable hepatocellular carcinoma (HCC) is poor, with median survival times of 40 mo for intermediate HCC (Barcelona Clinic Liver Cancer [BCLC] stage B) and 6-8 mo for advanced HCC (BCLC stage C). Although patients with early-stage HCC are usually suitable for therapies with curative intention, up to 70% of patients experience relapse within 5 years. In the past decade, the United States Food and Drug Administration has approved different immunogenic treatment options for advanced HCC, the most common type of liver cancer among adults. Nevertheless, no treatment is useful in the adjuvant setting. Since 2007, the multi-kinase inhibitor sorafenib has been used as a first-line targeted drug to address the increased mortality and incidence rates of HCC. However, in 2020, the IMbrave150 trial demonstrated that combination therapy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor [VEGF]) is superior to sorafenib, a single anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer monotherapy for HCC treatment. AIM: To conduct a systematic literature review to evaluate the evidence supporting the efficacy and safety of atezolizumab/bevacizumab as preferred first-line drug therapy over the conventional sorafenib or atezolizumab monotherapies, which are used to improve survival outcomes and reduce disease progression in patients with unresectable HCC and non-decompensated liver disease. METHODS: A comprehensive literature review was conducted using the PubMed, Scopus, ScienceDirect, clinicaltrials.gov, PubMed Central, Embase, EuropePMC, and CINAHL databases to identify studies that met the inclusion criteria using relevant MeSH terms. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and risk of bias (RoB) were assessed using the Cochrane RoB 2 tool and Sevis. RESULTS: In the atezolizumab/bevacizumab group, an improvement in overall tumor response, reduction of disease progression, and longer progression-free survival were observed compared to monotherapy with either sorafenib or atezolizumab. Hypertension and proteinuria were the most common adverse events, and the rates of adverse events were comparable to those with the monotherapy. Of the studies, there were two completed trials and two ongoing trials analyzed using high quality and low bias. A more thorough analysis was only performed on the completed trials. CONCLUSION: Treatment of HCC with atezolizumab/bevacizumab combination therapy was confirmed to be an effective first-line treatment to improve survival in patients with unresectable HCC and non-decompensated liver disease compared to monotherapy with either sorafenib or atezolizumab.