Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 molecular subgroups that exhibit different genomic alterations, gene expression profiles and response to treatment. We have previously shown a novel role for the MEK/MAPK pathway in specifically contributing to Sonic Hedgehog (SHH) MB tumor progression. Here, we compared the effect of the MEK inhibitor (MEKi) selumetinib to the more potent MEKi trametinib on tumor cell properties in vitro and assessed the effect of trametinib in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduced tumorsphere size, stem/progenitor cell proliferation and viability at much lower concentrations than selumetinib. RNA sequencing corroborated these findings with significant decreases in cell cycle and stem cell pathways concomitant with increases in pathways associated with cell differentiation and ciliopathies following MEKi treatment. Importantly, trametinib also decreased tumor growth and increased survival in vivo and this was accompanied by similar decreases in cell cycle related pathways as well as increases in IL6/JAK STAT3 signaling. Our study reveals a novel role for trametinib in effectively attenuating MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB.