Background: There is a myriad of microwave ablation (MWA) systems used in clinical settings worldwide for the management of liver cancer that offer a variety of features and capabilities. However, an analysis on which features and capabilities result in the most favorable efficacy and safety results has never been completed due to a lack of head-to-head comparisons. The aim of this study is to compare single-antenna and multiple-antenna MWA using radiofrequency ablation (RFA) as a common comparator in the treatment of very-early, early hepatocellular carcinoma (HCC) and ≤5 cm liver metastases. Methods: This network meta-analysis was performed according to PRISMA guidelines. PubMed, Cochrane, and Web of Science databases were searched for comparative studies. Complete ablation (CA) rate, local tumor progression-free (LTPF) rate, overall survival (OS), and major complication rate were assessed. Subgroup analyses were further performed based on synchronous or asynchronous MWA generators and tumor size (<2 cm or ≥2 cm). Results: Twenty-one studies (3424 patients), including 3 randomized controlled trials (RCTs) and 18 observational studies, met eligibility criteria. For CA, LTPF and major complications, as compared to single-antenna MWA, multiple-antenna MWA had relative risks (RRs) of 1.051 (95% CI: 0.987–1.138), 1.099 (95% CI: 0.991–1.246), and 0.605 (95% CI: 0.193–1.628), respectively. For 1-year and 3-year OS, as compared to single-antenna MWA, multiple-antenna MWA had odds ratios (ORs) of 0.9803 (95% CI: 0.6772–1.449) and 1.046 (95% CI: 0.615–1.851), respectively. Subgroup analysis found synchronized multi-antenna MWA was associated with significantly better LTPF by 22% (RR: 1.22, 95% CI 1.068, 1.421), and 21.4% (RR: 1.214, 95% CI 1.035, 1.449) compared with single-antenna MWA, and asynchronous multiple-antenna MWA, respectively, with more evident differences in larger tumors (≥2 cm). Conclusion: Multi-antenna and single-antenna MWA showed similar effectiveness for local treatment of liver tumors, but synchronous multi-antenna MWA exhibited better LTPF compared to other MWA approaches, particularly for larger liver tumors (≥2 cm). Large-scale RCTs should be further conducted.