Background Persistent pulmonary hypertension of the newborn (PPHN) causes morbidity and mortality in neonates. High-frequency ventilation (HFV), inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation (ECMO) are used when conventional treatment fails. This study aimed to identify echocardiographic predictors of progression to these therapies before clinical deterioration. Methods Echocardiographic parameters were compared for survival and need for ECMO, HFV, iNO, and prolonged mechanical ventilation (MV, ≥10 days). Results Of 63 neonates, 95% survived, with 14% requiring ECMO, 52% requiring HFV, 67% requiring iNO, and 35% requiring MV. The following echocardiographic indices reflecting left ventricular output were decreased in sicker infants: (1) A decreased ascending aortic velocity time integral indicated an increased likelihood of ECMO (p = 0.02), iNO (p = 0.01), or MV (p = 0.05), (2) Shorter transverse aortic arch antegrade ejection time indicated HFV (p < 0.01), iNO (p < 0.01), and MV (p = 0.03), (3) Absent or retrograde transverse aortic diastolic flow correlated with HFV (p = 0.01, iNO (p = 0.01), and MV (p < 0.01). These sicker patients were more likely to have smaller left ventricular end-diastolic areas (p < 0.03 for all) and right-to-left atrial shunting (ECMO, HFV, and MV). There were no differences in survival. Conclusions Decreased left ventricular size and output correlates with the need for advanced therapies in infants with PPHN. Early identification may allow more effective management and placement of neonates at risk.