Background and Objectives: 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 theLEPgene with the lack of glycemic control in T2DM patients on metformin therapy.Materials and Methods: 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 theLEPgene (rs7799039, rs2167270, and rs791620).Results: Serum leptin was significantly lower in T2DM patients with poor glycemic control (p< 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;p= 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;p= 0.001).Conclusions: Higher serum leptin and the GA genotype of the rs2167270 SNP of theLEPgene 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.