Therapeutic resistance in cancer remains a substantial barrier to effective and long-term treatment outcomes. According to recent research, cancer stem cell (CSC) populations and dysregulated autophagy play a key role in the development of resistance, which in turn causes tumor recurrence and metastasis. Since they affect vital pathways linked to autophagy and the maintenance of cancer stem cells (CSCs), microRNAs (miRNAs) are acknowledged as significant regulators of gene expression. By developing feedback loops and constitutively activating carcinogenic signaling pathways, miRNA dysregulation promotes cell stemness and aids in tumor metastasis and therapeutic resistance. More significantly, certain miRNAs might be viable targets for cancer treatment, diagnosis, and prognosis. The intricate relationships between miRNAs, failed autophagy, and cancer stem cell-driven resistance mechanisms in cancer treatment are discussed in this chapter. We discuss how certain miRNAs can either promote or inhibit autophagy, hence influencing cellular survival in response to targeted and chemotherapeutic therapies. Furthermore, we highlight how miRNAs control the properties of CSCs, such as self-renewal, plasticity, and the epithelial-to-mesenchymal transition (EMT), all of which enhance tumor resistance. In addition to discover a potential strategy for overcoming therapeutic resistance, research is currently being conducted on miRNA-based therapeutic approaches, such as miRNA mimics and inhibitors. Through innovative combination treatment approaches, integrating miRNA regulation with existing cancer therapies may improve therapeutic efficacy and reduce relapse rates. This chapter explores the translational effects of miRNA-targeted therapies and offers novel concepts for addressing cancer resistance through the control of cancer stem cells and autophagy.