Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB. Display omitted •We identify neuroblastoma models as sensitive to SHP2 inhibition•SHP099 sensitivity is correlated with low expression of neurofibromin (NF1)•SHP2 inhibitors inhibit pERK in neuroblastoma cells better than in normal cells•NF1 mutation/expression may predict SHP2 inhibitor response in neuroblastoma In this paper, Cai et al. demonstrate that high-risk neuroblastomas with low NF1 expression are sensitive to SHP2 inhibitors, which may have treatment advantages over MEK inhibitors. Targeting SHP2 blocks neuroblastoma tumor growth. As several SHP2 inhibitors are in clinical trials, SHP2 inhibitors may benefit high-risk NB patients.