Glioblastoma (GB) remains a major challenge owing to its extremely aggressive nature and resistance to conventional therapies. This review focuses on the intricate roles of progenitor cells, microglia, and non-coding RNAs (ncRNAs) in orchestrating GB pathogenesis and therapy resistance. Glioma stem cells (GSCs), derived from progenitor cells, are important drivers of tumor initiation and recurrence and exhibit remarkable plasticity and resistance to treatment. Microglia, the immune cells of the brain, are hijacked by GB cells to create an immunosuppressive microenvironment that supports tumor growth and resistance to therapy. Non-coding RNAs, including microRNAs and long noncoding RNAs, regulate multiple resistance mechanisms by modulating gene expression and influencing the interactions between progenitor cells and microglia. This review highlights new insights into these interconnected signaling pathways and explores potential therapeutic strategies targeting these molecular players to overcome treatment resistance and improve outcomes in patients with GB.