Despite depression being a major driver of morbidity and mortality, the majority of primary care patients remain undiagnosed, so this study aimed to assess the prevalence of depression and the association with demographic and clinical variables, genetic risk, and quality of life. The participants were presumably healthy model family medicine practice (MFMP) attendees between 30 and 65 years of age and recruited during a preventive check-up in 2019. Each of the 40 pre-selected MFMP pragmatically invited 30 attendees to voluntarily participate. They completed a questionnaire of demographic, clinical, and social determinants, as well as a three-generational family history. The results were analyzed using multivariable modelling to calculate the associations with signs of depression. A modified Scheuner method was used to calculate the level genetic risk level using family history. Of 968 participants, aged 42.8 ± 8.6 years, 627 (64.8%) were women. The prevalence of depression was 4.1%. Signs of depression were negatively associated with health-related quality of life score, in particular in the domains of self-care (p = 0.001) and anxiety/depression (p < 0.001). Depression was also associated with predicted high risk for comorbidities given the family history (p = 0.030). Primary care directed at improving patients’ quality of life should implement more widespread screening for mental health disorders. Family history for disease even beyond depression can be used by physicians as an important primary prevention tool.