<p>Dead-box RNA helicases (DDXs) are a family of proteins with roles in RNA metabolism, regulating processes such as RNA splicing, translation, and ribosome assembly. Recently, their functions have expanded to include essential roles in autophagy—a cellular degradation pathway crucial for maintaining homeostasis—and oncogenesis, notably in glioblastoma. Glioblastoma is characterized by rapid proliferation, invasiveness, and resistance to conventional treatments, making it a formidable clinical challenge. Emerging evidence suggests that specific DDXs may influence multiple key pathways that contribute to gliomagenesis, the process of glioma formation including cell cycle regulation, epithelial-to-mesenchymal transition (EMT), angiogenesis, immune modulation, anti-inflammatory signaling, and autophagy. Understanding the dual role of DDXs in autophagy and gliomagenesis may reveal potential therapeutic targets, as manipulating these helicases could disrupt cancer cell adaptation mechanisms and slow tumor progression. We have also explored the potential of autophagy inhibitors to enhance the efficacy of current therapeutics. This review aims to explore the implications of DDXs in glioblastoma, focusing on their interactions with cellular pathways, and highlights the need for further investigation into how these proteins could be leveraged for therapeutic benefit.</p>