Background: Type 2 diabetes mellitus (T2DM) and its associated complications are of public health concern. Metformin is the most common pharmacological T2DM treatment, distributed through organic cation transporters (OCTs). The solute transporter family 22A1 (SLC22A1) gene encodes OCT1, and its variants may play a role in glycemic control. This study analyzed seven SLC22A1 gene variants and their potential association with glycemic control in patients from Northern Mexico with T2DM undergoing metformin monotherapy. Methods: This cross-sectional study included 110 patients. We analyzed HbA1c values as a continuous variable and according to glycemic control categories (<7% vs. ≥7%). DNA from blood samples was genotyped using genotyping assays based on real-time PCR and PCR-RFLP. Results: Patients with GG or AA rs628031 genotypes were 2.7 times more likely to have inadequate glycemic control than those with the GA genotype (p = 0.042). We analyzed the combination of rs628031 and rs622342 as diplotypes. The relation between HbA1c and these diplotypes was influenced by BMI and the metformin dose. Carriers of at least one minor allele of A-rs628031 and C-rs622342 had lower HbA1c values than individuals homozygous for the major allele in both genes. Conclusions: The rs628031 and rs622342 variants are associated with lower HbA1c levels in T2DM patients. Larger studies are needed to confirm these associations.