Trisomy 21 (Down Syndrome) may lead to multiple hematological and hepatobiliary manifestations including the development of transient abnormal myelopoiesis. While many cases resolve, transient abnormal myelopoiesis may lead to significant morbidity and mortality in a small percentage of patients. This condition may present a diagnostic challenge for physicians and currently there is only limited data on effective treatments, particularly with low blast percent transient abnormal myelopoiesis. We present a case of a neonate with trisomy 21 and multiple congenital anomalies who consequently developed hepatic failure with evidence of non-cirrhotic portal hypertension likely due to transient abnormal myelopoiesis. This clinical scenario highlights the need for additional evaluation for transient abnormal myelopoiesis associated hepatic disorder and possibly hepatic sinusoidal occlusive syndrome among trisomy 21 neonates particularly with low blast percentage.