<p>Type 2 diabetes mellitus (T2DM) and depression frequently co-occur, contributing to worsened clinical outcomes. Emerging evidence suggests shared genetic mechanisms may underlie this comorbidity. The Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) gene, involved in Wnt signaling, has been implicated in both metabolic and neuropsychiatric pathways. This study aimed to investigate the association of LRP5 polymorphisms with depression in individuals with T2DM. A total of 200 participants with T2DM were recruited, including 75 with depression and 125 without depression. Four LRP5 single-nucleotide polymorphisms (SNPs)—<i>rs11228303, rs3758644, rs7102273,</i> and <i>rs12363572</i>—were genotyped. Allelic and genotypic distributions were compared between groups. Haplotype and linkage disequilibrium (LD) analyses were performed using SHEsis (a web-based platform for analyses of LD). No significant differences were observed in individual SNP allele or genotype frequencies between groups. Genotype modeling (codominant, dominant, and recessive) for <i>rs11228303</i> showed no association with depression. However, haplotype analysis identified the <i>T</i>–<i>C</i>–<i>C</i>–<i>C</i> haplotype is maximally associated with increased risk of depression in diabetics (<i>P</i> = 0.026; OR = 4.388; 95% CI 1.065–18.075 after adjustment with covariates <i>P</i> = 0.784 and OR = 1.955 (0.694–5.507), while the <i>C</i>–<i>C</i>–<i>C</i>–<i>C</i> and T–C–T–C haplotype showed a protective trend. LD analysis revealed strong D′ values among SNP pairs but low r² values, suggesting shared haplotype structure with weak allelic correlation. While no association was found at the individual SNP level, haplotype analysis suggests that specific LRP5 variant combinations may influence susceptibility to depression in T2DM. The findings highlight the utility of haplotype-based approaches in uncovering genetic contributions to complex comorbid conditions.</p>