Simple Summary: Colorectal cancer is a significant cause of cancer-related deaths in the US and the fourth most common malignancy. Percutaneous thermal ablation (TA) is considered a potential alternative to partial hepatectomy in selected patients when eradication of all visible tumor with an ablative margin of greater than 5 mm is achieved. This systematic review and meta-analysis aimed to encapsulate the current clinical evidence concerning the associated risk of different thermal ablation margins for local tumor progression (LTP), while also providing definite evidence concerning the optimal thermal ablation margin. By pooling the available evidence from 21 studies consisting of 2005 participants and 2873 ablated colorectal liver metastases (CLM), this meta-analysis solidifies that a minimal ablation margin over 5 mm is the minimum critical endpoint required, whereas a minimal margin of at least 10 mm yields optimal local tumor control after TA of CLMs. Background: Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the US. Thermal ablation (TA) can be a comparable alternative to partial hepatectomy for selected cases when eradication of all visible tumor with an ablative margin of greater than 5 mm is achieved. This systematic review and meta-analysis aimed to encapsulate the current clinical evidence concerning the optimal TA margin for local cure in patients with colorectal liver metastases (CLM). Methods: MEDLINE, EMBASE, and the CENTRAL databases were systematically searched from inception until 1 May 2023, in accordance with the PRISMA Guidelines. Measure of effect included the risk ratio (RR) with 95% confidence interval (CI) using the random-effects model. Results: Overall, 21 studies were included, comprising 2005 participants and 2873 ablated CLMs. TA with margins less than 5 mm were associated with a 3.6 times higher risk for LTP (n = 21 studies, RR: 3.60; 95% CI: 2.58–5.03; p-value < 0.001). When margins less than 5 mm were additionally confirmed by using 3D software, a 5.1 times higher risk for LTP (n = 4 studies, RR: 5.10; 95% CI: 1.45–17.90; p-value < 0.001) was recorded. Moreover, a thermal ablation margin of less than 10 mm but over 5 mm remained significantly associated with 3.64 times higher risk for LTP vs. minimal margin larger than 10 mm (n = 7 studies, RR: 3.64; 95% CI: 1.31–10.10; p-value < 0.001). Conclusions: This meta-analysis solidifies that a minimal ablation margin over 5 mm is the minimum critical endpoint required, whereas a minimal margin of at least 10 mm yields optimal local tumor control after TA of CLMs. [ABSTRACT FROM AUTHOR]