The dysregulated expression of the transcription factor (TF) Sry-related HMG box 9 (SOX9) has been extensively correlated with various biological effects, including the initiation and progression of cancer. Differential expression of SOX9 has been positively correlated with cancer cell growth, invasion, migration, metastasis, and therapy resistance. Studies showed that expression of SOX9 affects the expression of various miRNAs and vice versa, resulting in the development of cancer drug resistance. However, modulating the expression of SOX9 reverses drug resistance by modulating the expression of miRNAs. Therefore, in this review, we summarize current research focusing on SOX9 as a cancer therapeutic target and a prognostic biomarker of cancer drug resistance.