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Background: We sought to assess the safety and efficacy of endovenous thermal ablation (EVTA) in treating large great saphenous veins (GSV) > 12 mm in diameter. Methods: We performed a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 for comparative and noncomparative studies depicting EVTA in the treatment of GSV > 12 mm. Primary endpoints included GSV occlusion, technical success, deep vein thrombosis (DVT), and endovenous heat-induced thrombosis (EHIT). We conducted a comparative analysis between GSV > 12 mm and < 12 mm and a meta-regression analysis for two sets of studies, one including the whole dataset, containing treatment arms of comparative studies with GSV < 12 mm and one exclusively for GSV > 12 mm. Results: Seven studies, including 2564 GSV, depicting radiofrequency (RFA) and endovenous laser ablation (EVLA) were included. GSV > 12 mm occlusion, technical success, DVT, and EHIT estimates were 95.9% (95% CI: 93.6–97.8), 99.9% (95% CI: 98.9–100.0), 0.04% (95% CI: 0.0–3.4), and 1.6% (95% CI: 0.3–3.5). Meta-regression revealed a negative association between GSV diameter and occlusion for both the whole dataset ( p < 0.01) and the > 12 mm groups ( p = 0.04), GSV diameter and technical success for both groups ( p < 0.01), ( p = 0.016), and GSV diameter and EHIT only for the whole dataset ( p = 0.02). The comparative analysis between GSV < 12 mm and GSV > 12 mm displayed an occlusion estimate of OR 1.79 (95% CI: 1.25–2.56) favoring small GSV. Conclusion: Whereas we have displayed excellent occlusion and technical success results for the EVTA of GSV > 12 mm, our analysis has illustrated the unfavorable impact of GSV diameter on occlusion, technical success, and EHIT outcomes regardless of the 12 mm threshold. Potential parameter or device adjustments in a diameter-oriented fashion could further enhance outcomes.