Glioblastoma (GB) is an aggressive brain tumor characterized by marked radioresistance and poor clinical outcomes. MicroRNAs (miRNAs) are key post-transcriptional regulators implicated in tumor progression and therapeutic response. Here, we investigated radiation-induced miRNA modulation in patient-derived cancer stem-like cell (CSLC) neurospheres exposed to internal radionuclide therapy using rhenium-188-loaded lipid nanocapsules (¹⁸⁸Re-LNC). MiRNA profiling following ¹⁸⁸Re-LNC treatment identified miR-22-3p, miR-197-3p, and miR-574-3p as potential candidates for functional characterization. Lentiviral-mediated overexpression in U87MG cells revealed distinct phenotypes, with miR-22-3p promoting proliferation and clonogenic survival, whereas miR-197-3p primarily enhanced migratory capacity while miR-574-3p had little effect on either phenotype. In an orthotopic murine xenograft model, miR-22-3p and miR-197-3p overexpression accelerated tumor progression and was associated with reduced survival. Notably, upon ¹⁸⁸Re-LNC treatment, miR-22-3p-expressing tumors exhibited pronounced radioresistance, with a complete absence of long-term survivors, while miR-197-3p-expressing tumors remained responsive to therapy. AntagomiR-mediated inhibition of miR-22-3p restored radiosensitivity in vitro and was accompanied by upregulation of the DNA demethylase TET1 that is identified here as a candidate functional target of miR-22-3p. Together, these findings identify miR-22-3p as a critical mediator of GB radioresistance and miR-197-3p as a driver of invasion, supporting their relevance as therapeutic targets and predictive biomarkers to improve radiotherapy stratification and efficacy in GB.