Hyperhomocysteinemia or systemic elevation of homocysteine is a metabolic condition that has been linked to multiple neurological disorders where inflammation plays an important role in the progression of the disease. However, it is unclear whether hyperhomocysteinemia contributes to disease pathology by inducing an inflammatory response. The current study investigates whether exposure of primary cultures from rat and mice cortical neurons to high levels of homocysteine induces the expression and release of the proinflammatory prostanoid, Prostaglandin E2 (PGE2). Using enzymatic assays and immunoblot analysis we show concurrent increase in the activity of cytosolic phospholipase A2 (cPLA2) and level of cyclooxygenase‐2 (COX2), two enzymes involved in PGE2 biosynthesis. The findings also show an increase in PGE2 release from neurons. Pharmacological inhibition of GluN2A‐containing NMDAR (GluN2A‐NMDAR) with NVP‐AAM077 significantly reduces homocysteine‐induced cPLA2 activity, COX2 expression, and subsequent PGE2 release. Whereas, inhibition of GluN2B‐containing NMDAR (GluN2A‐NMDAR) with Ro 25‐6981 has no effect. Complementary studies in neuron cultures obtained from wild type and GluN2A knockout mice show that genetic deletion of GluN2A subunit of NMDAR attenuates homocysteine‐induced neuronal increase in cPLA2 activity, COX2 expression, and PGE2 release. Pharmacological studies further establish the role of both extracellular‐regulated kinase/mitogen‐activated protein kinase and p38 MAPK in homocysteine‐GluN2A NMDAR‐dependent activation of cPLA2‐COX2‐PGE2 pathway. Collectively, these findings reveal a novel role of GluN2A‐NMDAR in facilitating homocysteine‐induced proinflammatory response in neurons.