Neuroblastoma (NB) is the most common pediatric extracranial solid tumor arising from neural crest cells of the developing sympathetic nervous system. Despite marked advances in cancer treatment, the survival rate of high-risk NB remains unsatisfactory. As a key pro-inflammatory mediator regulating tumor microenvironment, prostaglandin E2 (PGE₂) promotes NB proliferation, angiogenesis, and immune evasion via acting on four G protein-coupled receptors, particularly the EP2 subtype. Recent studies have been vigorously focused on developing and evaluating compounds targeting PGE₂-regulated tumor inflammation in animal models of NB. In this review, we revisit these translational efforts and examine the feasibility of pharmacological inhibition of enzymes responsible for PGE₂ biosynthesis or its signaling receptors as emerging therapeutic strategies for NB. We also explore the potential downstream oncogenic pathways upon the activation of PGE₂ receptors, aiming to bridge the knowledge gap between tumorigenesis and the role of elevated PGE₂/EP2 signaling, which is widely observed in high-risk NBs.