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<i>Background and Objectives</i>: Type two diabetes mellitus (T2DM) is a chronic disease with debilitating complications and high mortality. Evidence indicates that good glycemic control delays disease progression and is hence a target of disease management protocols. Nonetheless, some patients cannot maintain glycemic control. This study aimed to investigate the association between serum leptin levels and several SNPs of the <i>LEP</i> gene with the lack of glycemic control in T2DM patients on metformin therapy. <i>Materials and Methods</i>: In a hospital-based case-control study, 170 patients with poor glycemic control and 170 patients with good glycemic control were recruited. Serum leptin was measured. Patients were genotyped for three SNPs in the <i>LEP</i> gene (rs7799039, rs2167270, and rs791620). <i>Results</i>: Serum leptin was significantly lower in T2DM patients with poor glycemic control (<i>p</i> < 0.05). In multivariate analysis, serum leptin levels significantly lowered the risk of having poor glycemic control (OR = 0.985; CI: 0.976–0.994; <i>p</i> = 0.002); moreover, the GA genotype of rs2167270 was protective against poor glycemic control compared to the GG genotype (OR = 0.417; CI: 0.245–0.712; <i>p</i> = 0.001). <i>Conclusions</i>: Higher serum leptin and the GA genotype of the rs2167270 SNP of the <i>LEP</i> gene were associated with good glycemic control in T2DM patients on metformin therapy. Further studies with a larger sample size from multiple institutions are required to validate the findings.