Existing data suggest subendocardial ischemia in preterm infants with patent ductus arteriosus (PDA) and alterations in cardiac function after indomethacin administration. This study aimed to explore the evolution of left ventricular function by conventional echocardiography and speckle-tracking echocardiography (STE) and to ascertain the interrelationship with coronary flow indices in response to indomethacin. A prospective observational study was performed with preterm infants receiving indomethacin for medical closure of PDA. Serial echocardiography was performed, and the results were analyzed using analysis of variance. Intra- and interobserver variability was assessed using the intraclass correlation coefficient. Indomethacin was administered to 18 infants born at a median gestational age of 25.8 weeks (interquartile range [IQR], 24.2–28.1 weeks) with a birth weight of 773 g (IQR, 704–1,002 g). The median age of the infants was 7.5 days (IQR, 4–17). Global longitudinal strain (GLS) values significantly decreased immediately after indomethacin infusion (preindomethacin GLS, −19.1 ± 2.4 % vs. −15.9 ± 1.7 %; p < 0.0001) but had improved at reassessment after 1 h (−17.4 ± 1.8 %). Conventional echocardiographic indices did not show significant alterations. A significant increase in arterial resistance in the coronary vasculature from 1.7 to 2.4 mmHg/cm/s was demonstrated. A significant correlation was noted between peak systolic GLS and flow resistance in the coronary vasculature. Significant changes in myocardial indices were observed immediately after indomethacin infusion. Compared with conventional methods, STE is a more sensitive tool to facilitate understanding of hemodynamics in preterm infants.