Background: Chagas disease is an endemic protozoan disease with high prevalence in Latin America. Of those infected, 20–30% will develop chronic Chagas cardiomyopathy (CCC) however, prediction using existing clinical criteria remains poor. In this study, we investigated the utility of left ventricular (LV) echocardiographic speckle-tracking global longitudinal strain (GLS) for early detection of CCC. Methods and results: 139 asymptomatic T. cruzi seropositive subjects with normal heart size and normal LV ejection fraction (EF) (stage A or B) were enrolled in this prospective observational study and underwent paired echocardiograms at baseline and 1-year follow-up. Progressors were participants classified as stage C or D at follow-up due to development of symptoms of heart failure, cardiomegaly, or decrease in LVEF. LV GLS was calculated as the average peak systolic strain of 16 LV segments. Measurements were compared between participants who progressed and did not progress by two-sample t-test, and the odds of progression assessed by multivariable logistic regression. Of the 139 participants, 69.8% were female, mean age 55.8 ± 12.5 years, with 12 (8.6%) progressing to Stage C or D at follow-up. Progressors tended to be older, male, with wider QRS duration. LV GLS was −19.0% in progressors vs. –22.4% in non-progressors at baseline, with 71% higher odds of progression per +1% of GLS (adjusted OR 1.71, 95% CI 1.20–2.44, p = 0.003). Conclusion: Baseline LV GLS in participants with CCC stage A or B was predictive of progression within 1-year and may guide timing of clinical follow-up and promote early detection or treatment.