Background: Ion channel-mediated cytosolic Ca2+ oscillations play a crucial role in promoting the growth of glioblastoma, a tumor of poor prognosis. Here, we have studied the roles of Ca-alphaT and Slowpoke ion channels in a Drosophila melanogaster glioblastoma model. Although their mammalian orthologs have been implicated in glioblastoma cell viability in vitro, their oncogenic potential remains uncharacterized in a complex in vivo context. Results: We show that glial-specific RNAi targeting Ca-alpha1T and Slowpoke in gliomas reduces glioma cell number and membrane extension and decreases glioma cell calcium activity and downstream activation of PI3K and pRIII/pERK signaling. Moreover, Slowpoke knockdown significantly extends glioma fly survival to near-control values and improves glioma-associated neurodegeneration. RNAseq transcriptomic analysis reveals shared regulation by both channels of pathways involved in metabolic rewiring, cell adhesion and excitatory neurotransmission, while uncovering distinct effects on synaptic function. Conclusions: Both Ca-alpha1T and Slowpoke are essential for pro-tumorigenic calcium-dependent signaling in Drosophila gliomas. Common effects observed upon gene knockdown support a coordinated function for these channels at the plasma membrane. Nevertheless, their distinct impacts on survival and gene expression profiles highlight non-redundant roles. Notably, Slowpoke knockdown promotes increased survival and neuroprotection, associated with the repression of synaptic genes aberrantly upregulated in gliomas, thereby identifying Slowpoke as a promising therapeutic target in glioblastoma.