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TGF-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3 in glioblastoma has not been defined yet. Here we studied the expression and functional role of endogenous and exogenous TGF-β3 in in vitro and in vivo models of glioblastoma. TGF-β3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β1 or TGF-β2 in most cell lines. Inhibition of TGF-β3 mRNA expression by ISTH2020 and ISTH2023, two different isoform-specific phosphorothioate Locked Nucleic Acid- (LNA) modified antisense oligonucleotide gapmers, blocks down-stream SMAD-2 and SMAD-1/5 phosphorylation in human LN-308 cells, without affecting TGF-β1 and TGF-β2 mRNA expression or protein levels. Moreover, inhibition of TGF-β3 mRNA reduces invasiveness in vitro. Interestingly, depletion of TGF-β3 also attenuates signaling evoked by TGF-β1 or TGF-β2. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β3 as well of the down-stream target, PAI-1, was reduced while TGF-β1 and TGF-β2 levels were unaffected following treatment with a TGF-β3-specific antisense oligonucleotide. We conclude that TGF-β3 might function as a gatekeeper controlling down-stream signaling despite high expression of TGF-β1 and TGF-β2 isoforms. Targeting TGF-β3 in vivo represents a promising strategy interfering with aberrant TGF-β signaling in glioblastoma.