Selectins and their ligands have been implicated in tumor growth and progression in carcinomas, but their role in neuroblastoma has not been systematically examined. In the current study we evaluated L-, P- and E-selectin binding to neuroblastoma cells and the expression of some of their known ligands, namely CD44, CD24 and P-selectin glycoprotein ligand-1 (PSGL-1). Genetic loss of PSGL-1 or CD24 and pharmacological inhibition of P-selectin reduced P-selectin binding to neuroblastoma cells in vitro. Targeting P-selectin using specific antibodies promoted a significant reduction in the growth of neuroblastoma tumors in vivo. In mechanistic studies binding of P-selectin to neuroblastoma cells activated Src and several other pro-survival kinases such as ERK1, AKT, FAK and p38. Interestingly, comparative mass single cell cytometry (CyTOF) analyses revealed considerable intra- and inter-cell line heterogeneity with respect to response to P-selectin binding. Additionally, the downstream response to all selectins showed general similarity. Our findings reported here not only provide pre-clinical evidence in support of therapeutic targeting of P-selectin, but also highlight the heterogeneity in response of tumor cells to P-selectin binding. These observations provide the basis for combining P-selectin inhibition with other targeted therapies for neuroblastoma.