Introduction: Chagas cardiomyopathy (ChC) is highly stigmatized, and the presence of depressive symptoms may be a common feature. However, its determinants remain unclear. Therefore, the present study aimed to verify the prevalence of depression and the clinical, echocardiographic, functional, and quality of life factors associated with depressive symptoms in patients with ChC and predominantly preserved cardiac function. Methods: Thirty-five patients with ChC (aged 40 to 60 years, 66% men, NYHA I-III) were evaluated by echocardiography, cardiopulmonary exercise testing, 6-minute walk test (6MWT), and Mini-Mental State Examination. Physical activity level was assessed using the Human Activity Profile (HAP) and health-related quality of life was assessed using the Short-Form Health Survey (SF-36). Depressive symptoms were evaluated using the Beck Depression Inventory. A cutoff point greater than 9 was indicative of depression. Results: Depression was detected in 13 patients (37%). In the univariate analysis, female sex, NYHA functional class, body mass index, HAP score, mental summary of SF-36, peak oxygen uptake, and 6MWT distance were associated with depressive symptoms. The final model showed that only the HAP score (B = -0.533; 95% confidence interval [CI]: -0.804 to -0.262) and SF-36 mental summary (B = -0.269; 95% CI: -0.386 to -0.153) remained as independent predictors of depressive symptoms in patients with ChC. Conclusions: Depression was prevalent in patients with ChC and predominantly preserved cardiac function. Physical activity and mental health were independent risk factors for depressive symptoms.