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Background: Increasing evidence has shown that an elevated a level of homocysteine (Hcy) in the blood is related to several diseases. Over the last few years, studies have demonstrated creatine (Cr) synthesis and Hcy formation are metabolically connected; and Cr supplementation can decrease Hcy blood levels in different situations. This data however is inconsistent and still controversial. Objective: The aim of this critical review with meta-analysis was to discuss and ascertain the effects of Cr supplementation on blood Hcy levels. Method: A review was conducted according to the PRISMA guidelines using PubMed Discuss and Scielo online databases to identify relevant studies through November 2015. RevMan was used to calculate the effect size of the change in Hcy plasma/serum concentration from baseline to post-supplementation with Cr vs. placebo groups. Weighted mean differences were calculated using random effect models. Results: Cr supplemented trials were divided into two subgroups according to whether the experimental design included animals or humans participants. Overall, 14 studies were included in the meta-analysis. The six rodent included studies reported decreased plasma Hcy concentration after Cr supplementation with a mean effect size equal to −2.43 μmol/l (95% CI: 3.60, −1.26, P < 0.01). The humans studies involved 483 participants (242 Cr and 241 placebo supplemented subjects) and indicated no changes in plasma Hcy concentration after Cr supplementation compared to placebo (0.09 μmol/l, 95% CI: −0.47, 0.66, P = 0.18). Conclusions: Our data demonstrated Cr supplementation is effective in decrease Hcy blood concentration in rats; the same effect however, is not demonstrated humans studies. Human and rats particularities in Hcy metabolism and poorly controlled humans studies may contribute to the divergence of results.