Background: Molecular-targeted agents such as Lenvatinib and Sorafenib have improved survival outcomes in patients with hepatocellular carcinoma (HCC). However, using these agents in the primary treatment for advanced HCC is still under debate, with limited literature comparing the therapeutic effects of Lenvatinib versus Sorafenib. Methods: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until 10th February 2023. Results: A total of 8 studies with 1995 patients (955 Lenvatinib vs. 1040 Sorafenib) were included in our analysis. The mean age of the patients in both groups was comparable (65 vs. 66) years. The overall survival was also comparable between the groups (HR = 0.83; 95%CI: 0.67-1.02; p = 0.08). However, progression-free survival (HR = 0.83; 95%CI: 0.77-0.89; p<0.00001) and time to progression (HR = 0.69; 95%CI: 0.51-0.93; p = 0.02) were significantly improved in the Lenvatinib group compared to Sorafenib. The pooled analysis showed that the treatment response evaluated through the Objective response rate (OR = 7.37; 95%CI: 1.86-29.20; p = 0.004) and Disease control rate (OR = 3.03; 95%CI: 0.98-9.30; p = 0.05) of the Lenvatinib group were better than those of the Sorafenib group. However, the likelihood of severe adverse events (OR = 1.76; 95%CI: 1.38-2.24; p <0.00001) was significantly higher in the Lenvatinib group compared with Sorafenib patients. In addition, among common adverse events, hypertension (HR = 2.68; 95%CI: 1.48-4.83; p = 0.001) and fatigue (HR = 2.53; 95%CI: 0.90-7.13) were significantly higher among Lenvatinib group compared to Sorafenib. Conclusions: In the primary treatment of advanced HCC, Lenvatinib significantly improves progression-free survival, time to progressions, and objective response rate. However, the likelihood of severe and common adverse events such as hypertension and fatigue are significantly higher after using Lenvatinib than Sorafenib.