Background/Objectives: Depression ranks among the most prevalent mental health disorders worldwide. Numerous studies have linked the C-1019G (rs6295) polymorphism in the serotonin 1A (5-HT1A) receptor gene to increased susceptibility to depression. In this study, sociodemographic variables and clinical characteristics were integrated with targeted genotyping of the C-1019G polymorphism to identify risk factors associated with depressive symptoms in a Mexican cohort. Methods: Sociodemographic and clinical data were collected from 257 volunteers (202 healthy controls, 55 with depressive symptoms). Genotyping for C-1019G was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Sociodemographic variables, clinical characteristics, and genotype frequencies were analyzed relative to Beck Depression Inventory II (BDI-II) scores. Results: BDI scores were significantly lower among males, participants aged < 40 years, unmarried individuals, and those with a high school education (p < 0.05). Females were three times more likely to exhibit depressive symptoms than males (p = 0.004; OR = 3.08). Compared with participants aged < 40 years, those aged 40–65 and >65 years were two (p = 0.026; OR = 2.19) and five times (p < 0.001; OR = 5.71) more likely to report depressive symptoms, respectively. Participants with type 2 diabetes mellitus had twice the odds of depressive symptoms (p = 0.025; OR = 2.38). Odds increased twelvefold among those with diabetes plus arterial hypertension (p < 0.001; OR = 12.25). Among males, the C/C genotype was observed exclusively in controls (p = 0.010). Furthermore, the genotypic distribution of this study population differed from that of European and Asian populations. Conclusions: These findings advance the understanding of depressive symptoms’ multifactorial etiology and may inform targeted screening and prevention strategies.