Background Depression is a common mental disorder in family practice with an impact on global health. The aim of this study is to provide insight in the trends of epidemiological measures as well as pharmacological treatments and comorbidities of depression. Methods A study using data from INTEGO, a family practice registration network in Flanders, Belgium. Trends in age-standardized prevalence and incidence of depression from 2000 to 2019 as well as antidepressant prescriptions in prevalent depression cases were analyzed with join point regression. Comorbidity profiles were explored using the Cochran-Armitage test and the Jonckheere-Terpstra test. Results We identified 538 299 patients older than 15 years during the study period. We found an increasing trend in the age-standardized prevalence of depression from 6.73 % in 2000 to 9.20 % in 2019. For the incidence of depression, a decreasing trend was observed from 2000 to 2015 with an incidence of 9.42/1000 in 2000 and 6.89/1000 in 2015, followed by an increasing trend from 2015 to 2019 (incidence of 13.64/1000 in 2019). The average number of chronic diseases per patient with depression increased significantly during the study period (from 1.2 to 1.8), and the proportion of patients relative to the whole study population that received at least one antidepressant prescription per year increased between 2000 and 2019 from 26.44% to 40.16%. Conclusions The prevalence of depression increases while the incidence sharply rises, but only in recent years. Patients with depression tend to have more comorbidities, making a multi-faceted approach to these patients more important.